JP5697657B2 - (Pyrazol-3-yl) -1,3,4-thiadiazol-2-amine and (pyrazol-3-yl) -1,3,4-thiazol-2-amine compounds - Google Patents

Description

  The present invention relates to compounds, compositions containing them, their use in therapy, eg, tuberculosis therapy, and methods of preparing such compounds.

Synthetic drugs for treating tuberculosis (TB) have been available for over half a century, but the incidence continues to rise worldwide. In 2004, it is estimated that 24,500 people developed active disease and nearly 5,500 people died every day from TB (World Health Organization, Global Tuberculosis Control: Survey, Planning, Financing. WHO Report. 2006, Geneva, Switzerland, ISBN 92-4 156314-1). Co-infection with HIV has boosted disease incidence (Williams, BG; Dye, C. Science, 2003, 301, 1535) and believes that the cause of death in 31% of AIDS patients in Africa is due to TB (Corbett, E.L .; Watt, CJ; Catherine, J .; Walker, N .; Maher D .; Williams, B. G .; Raviglione, MC; Dye, C. Arch) Intl. Med., 2003, 163, 1009, Sepkowitz, A.; Raffally, J.; Riley, T.; Kiehn, T.E .; Armstrong, D.Clin.Microbiol.Rev. 1995, 8, 180) . When combined with the emergence of multi-drug resistant strains of M. tuberculosis (MDR-TB), the scale of the problem is amplified. More than 10 years have passed since WHO declared a “global hygiene emergency” (World Health Organization, Global Tuberculosis Control: Surveillance, Planning, Financing. WHO Report 2006, GeneV, 92N Genet, 92). 156314-1).

  The limitations of tuberculosis treatment and prevention are well known. BCG, a currently available vaccine, was introduced in 1921 but cannot protect many people past their childhood. Currently, patients infected with active disease continue to take isoniazid (INH), rifampicin, pyrazinamide, ethambutol for 2 months followed by isoniazid and rifampicin for another 4 months. Daily administration is required and inadequate compliance causes the emergence and spread of multi-drug resistant strains that are difficult to treat. A recently published detailed report discusses various aspects of TB, including etiology, epidemiology, drug discovery, and vaccine development to date (Nature Medicine, Vol 13 (3), pages 263-312). .

  There is an urgent need for drugs that can be taken less frequently and that are more effective in short-term administration that can provide a high barrier to the emergence of resistance, that is, drugs that are effective against multi-drug resistant strains of TB. ing. Therefore, there is a need to discover and develop new chemicals that treat TB. (Ballell, L .; Field, RA; Duncan, K .; Young, RJ Antimicrob. Agents Chemother. 2005, 49, 2153 review recent synthetic lead compounds).

  Lipid metabolism is particularly important for mycobacteria and is a very effective target for the development of selective anti-tuberculosis drugs. The enzyme called “InhA” is NADH-dependent (depends on the reduced form of nicotinamide adenine dinucleotide), 2-transenoyl ACP (acyl carrier protein) reductase of the type 2 fatty acid synthesis (FASII) pathway by Mycobacterium tuberculosis It is. There is strong evidence that InhA is the primary target of the leading antituberculosis drug isoniazid (INH). Both clinical isolates overexpressing InhA and laboratory denatured mycobacteria are resistant to INH. INH inhibits InhA enzyme activity that induces the accumulation of C24-C26 saturated fatty acids and prevents the production of longer molecules including mycolic acid. This inhibition is associated with mycobacterial cell death.

  The importance of InhA has also been demonstrated by the use of temperature-sensitive mutants of InhA in Smegma, and changes to non-permissive temperatures result in rapid lysis and cell death.

  INH is a bactericidal drug, shows specific activity against Mycobacterium tuberculosis, and is part of first-line drug combination therapy for anti-tuberculosis treatment. INH is activated by KatG catalase in mycobacterial cells. The active form is believed to react covalently with NADH in the InhA active site to make an inhibitory adduct. X-ray structures with InhA bound to several inhibitors are available and are used in the design of new inhibitors.

  INH activated in vitro forms an adduct with the NAD (P) cofactor that binds to InhA and inhibits other enzymes such as InhA and DHFR (dihydrofolate reductase); The physiological relevance of action is clear in the case of enoyl reductase but has been shown to be largely unrelated in the case of DHFR; the potential of other possible targets of INH for the antitubercular activity of the drug The role seems to be minimal or nonexistent.

  Resistance to INH is associated with at least 5 different genes (KatG, InhA, ahpC, kasA, and ndh); although 60-70% resistant isolates are defective in the KatG gene, but less frequently Can bind directly to defects in the InhA structural gene or upstream promoter region (often with compensatory mutations in other genes).

InhA targeting agent that does not require activation by KatG interacts with the enzyme in a different manner than the NAD-INH complexes, also have a different pharmacological profile than INH, most current INH ^R It is expected that the (Isoniazid resistant) strain will be killed and replace the INH used in existing treatments for Mycobacterium tuberculosis.

World Health Organization, Global Tuberculosis Control: Surveyilance, Planning, Financing. WHO Report 2006, Geneva, Switzerland, ISBN 92-4 156314-1 Williams, B.M. G. Dye, C .; Science, 2003, 301, 1535 Corbett, E .; L. Watt, C .; J. et al. Catherine, J .; Walker, N .; Maher D .; Williams, B .; G. Raviglione, M .; C. Dye, C .; Arch. Intl. Med. , 2003, 163, 1009, Sepkowitz, A.M. Raffalli, J .; Riley, T .; Kiehn, T .; E. Armstrong, D .; Clin. Microbiol. Rev. 1995, 8, 180 Nature Medicine, Vol 13 (3), pages 263-312 Ballell, L.M. Field, R .; A. Duncan, K .; Young, R .; J. et al. Antimicrob. Agents Chemother. 2005, 49, 2153

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In the formula:
X is N and Y is CR ⁵ ; or X is C and Y is any of S;
Z is selected from N and CH;
R ¹ is selected from H and Me;
R ² is selected from H, OH, OMe and Me;
Each R ³ is independently selected from C _1-3 alkyl, F, Cl, Br, CF ₃ and NH ₂ ;
R ⁴ is selected from Me, CF ₃ , NO ₂ and CHF ₂ ;
R ⁵ is selected from H, Me and CHF ₂ ;
R ⁶ is selected from H and Me; and p is 0-3.

  In one aspect of the invention, there is provided a compound of formula (I) as defined above.

  The present invention further provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents.

  In one aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers, excipients or diluents.

  The present invention also provides a method of treating tuberculosis in mammals, particularly humans, which comprises an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for a mammal in need of such treatment. Including administration of salt.

  In one aspect of the invention, there is provided a method of treating tuberculosis in a mammal, particularly a human, comprising administering an effective amount of a compound of formula (I) to the mammal in need of such treatment.

  The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

  In one aspect of the invention, there is provided a compound of formula (I) for use in therapy.

The present invention still further provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of tuberculosis in mammals, particularly humans.
In one aspect of the invention, there is provided a compound of formula (I) for use in the treatment of tuberculosis in mammals, particularly humans.

  The present invention still further provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of tuberculosis in mammals, particularly humans.

  One aspect of the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for use in the treatment of tuberculosis in mammals, particularly humans.

  The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers for use in the treatment of tuberculosis in mammals, particularly humans. A pharmaceutical composition comprising an excipient or diluent is provided.

  In one aspect of the invention, a compound of formula (I) for use in the treatment of tuberculosis in a mammal, particularly a human, and one or more pharmaceutically acceptable carriers, excipients or diluents. A pharmaceutical composition is provided.

In one aspect of the invention, the absolute stereochemistry of a compound of formula (I) or a pharmaceutically acceptable salt thereof is represented by formula (I ^* ).

In one aspect of the invention, R ² is selected from H, OH and Me.

In one aspect of the invention, when X is N and Y is CR ⁵ , R ² is selected from H and Me.

  In one aspect of the invention, X is C and Y is S.

In one aspect of the invention, R ¹ is Me. In a further aspect of the invention, R ¹ is Me and R ² is H, OH or OMe. In yet a further aspect of the invention, R ¹ is Me and R ² is OH. In embodiments of the invention in which R ¹ is Me and R ² is H, OH or OMe, the carbon atom to which R ¹ and R ² are attached (labeled with “*” in the above formula (I ^* )) ) Is the chiral center. Such an embodiment may be in the form of a mixture of isomers, for example a racemic mixture of enantiomers, or in the form of a single isomer. In one embodiment, the invention provides a single isomer of the compound of the invention, wherein R ¹ is Me and R ² is H, OH or OMe. In another embodiment, the invention provides a single isomer of the compound of the invention, wherein R ¹ is Me and R ² is OH. In a further embodiment, the present invention provides a compound of formula (I) having the absolute stereochemistry shown in formula (I ^* ) or a pharmaceutically acceptable salt thereof, wherein R ¹ is Me and R ² is OH. In yet a further embodiment, the present invention provides a compound of formula (I) having the absolute stereochemistry shown in formula (I ^* ) or a pharmaceutically acceptable salt thereof, wherein R ¹ is Me And R ² is H, OH or OMe.

In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the asymmetric center marked * in the following formula (IS) is in the (S) configuration .

  In one aspect, compounds that can be used in the present invention include the compounds mentioned in the examples and their pharmaceutically acceptable salts.

In one aspect of the invention, at least one R ³ group is selected from C _1-3 alkyl, CF ₃ and NH ₂ . In one embodiment, p is 1 and R ³ is selected from C _1-3 alkyl, CF ₃ and NH ₂ . In a further embodiment, P is 2, one R ³ group is selected from C _1-3 alkyl, CF ₃ and NH ₂ and the other R ³ groups are C _1-3 alkyl, F, Cl, Br, CF Selected from ₃ and NH ₂ . In still further embodiments, p is 3, one R ³ group is selected from C _1-3 alkyl, CF ₃ and NH ₂ , and the other two R ³ groups are C _1-3 alkyl, F, Cl, Selected from Br, CF ₃ and NH ₂ . In a further aspect of the invention, at least two R ³ groups are F. In one embodiment, p is 2 and both R ³ groups are F. In a further embodiment, p is 3, the two R ³ groups are F, and the remaining R ³ groups are selected from C _1-3 alkyl, F, Cl, Br, CF ₃ and NH ₂ . For example, two R ³ groups are F and the remaining R ³ groups are Me.

In another aspect, compounds that can be used in the present invention include: That is,
1 5- [1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -N- (1-{[2- (trifluoromethyl) phenyl] methyl} -1H-pyrazol-3-yl ) -1,3,4-thiadiazol-2-amine 2 N- {1-[(2,5-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl) -1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 3 N- {1-[(2-bromophenyl) methyl] -1H-pyrazol-3-yl} -5 [1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 4 N- {1-[(2,5-dichlorophenyl) methyl] -1H -Pyrazol-3-yl} -5- [1- (3 -Methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 5 N- {1-[(2-bromophenyl) methyl] -1H-pyrazol-3-yl}- 5- [1- (3-Methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 6 5- [1- (3,5-dimethyl-1H-pyrazole-1 -Yl) ethyl] -N- {1-[(2-fluorophenyl) methyl] -1H-pyrazol-3-yl} -1,3,4-thiadiazol-2-amine 7 N- {1-[(3 -Chloro-2-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazole -2-amine 8 N- (1-{[2,5 -Bis (trifluoromethyl) phenyl] methyl} -1H-pyrazol-3-yl) -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4 Thiadiazol-2-amine 9 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- (1-{[5-fluoro-2- (trifluoromethyl) phenyl] methyl } -1H-pyrazol-3-yl) -1,3,4-thiadiazol-2-amine 10 N- {1-[(2,3-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5 -[1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 11 N- (1-{[2-chloro-5- (trifluoro Methyl) phenyl] methyl}- H-pyrazol-3-yl) -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 12 N- {1- [ (2,6-Difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazole -2-amine 13 N- {1-[(2-fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ) Ethyl] -1,3,4-thiadiazol-2-amine 14 N- {1-[(3-chloro-2-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- ( 3-methyl-1H-pyrazol-1-yl) Til] -1,3,4-thiadiazol-2-amine 15 N- {1-[(2,3-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl) -1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 16 N- {1-[(2,3-difluorophenyl) methyl] -1H-pyrazol-3-yl}- 5- [1- (4-Methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazol-2-amine 17 N- {1-[(2-chloro-4-fluorophenyl) ) Methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 18 N- {1-[(2-Chloro-4-fluoroph Nyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 19 N- { 1-[(2-Chloro-6-fluorophenyl) methyl] -5-methyl-1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl ] -1,3,4-thiadiazol-2-amine 20 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- {1-[(2-methylphenyl) methyl ] -1H-pyrazol-3-yl} -1,3,4-thiadiazol-2-amine 21 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- [1 -(Phenylmethyl) -1H-pyrazole-3- Yl] -1,3,4-thiadiazol-2-amine 22 N- {1-[(6-chloro-2-fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [ 1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 23 N- {1-[(2-chloro-6-fluoro-3-methyl) Phenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 24 5 -[1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -N- {1-[(2-fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl}- 1,3,4-thiadiazol-2-amine 5 N- {1-[(2-fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (4-methyl-1,3-thiazol-2-yl) ethyl ] -1,3,4-thiadiazol-2-amine 26 N- {1-[(5-amino-2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5) -Dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 27 N- {1-[(3-amino-2-methylphenyl) methyl] -1H-pyrazole-3 -Yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 28 N- {1-[(2-chloro- 6-Fluorophenyl) methyl] -1H-pyrazole 3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 29 N- {1-[(2-chloro -6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazole-2 -Amine 30 1- [5-({1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl]- 1- (4-Methyl-1,3-thiazol-2-yl) ethanol 31 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- { 1- [4- (trifluoromethyl) -1,3-thia Ol-2-yl] ethyl} -1,3,4-thiadiazol-2-amine 32 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl}- 5-[(4-Methyl-1,3-thiazol-2-yl) methyl] -1,3,4-thiadiazol-2-amine 33 N- {1-[(3-chloro-2-fluorophenyl) methyl ] -1H-pyrazol-3-yl} -5- [1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazol-2-amine 34 N- {1 -[(4-Chlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazole- 2-Amine 35 5- [1- (3,5-dimethyl) -1H-pyrazol-1-yl) ethyl] -N- (1-{[4- (trifluoromethyl) phenyl] methyl} -1H-pyrazol-3-yl) -1,3,4-thiadiazole-2- Amine 36 N- {1-[(2-chloro-5-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) Ethyl] -1,3,4-thiadiazol-2-amine 37 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3,5 -Dimethyl-1H-pyrazol-1-yl) methyl] -1,3-thiazol-2-amine 38 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl } -5- [1- (3-Methyl Ru-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 39 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazole-3- Yl} -5-[(3-methyl-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine 40 N- {1-[(2-chlorophenyl) methyl] -1H- Pyrazol-3-yl} -5- [1- (5-methyl-3-nitro-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 41 N- {1- [ (2-Chlorophenyl) methyl] -1H-pyrazol-3-yl} -5- {1- [3- (difluoromethyl) -5-methyl-1H-pyrazol-1-yl] ethyl} -1,3,4 -Thiadiazol-2-amine 4 N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4 Thiadiazol-2-amine 43 5- {1- [3- (difluoromethyl) -5-methyl-1H-pyrazol-1-yl] ethyl} -N- [1- (phenylmethyl) -1H-pyrazole-3- Yl] -1,3,4-thiadiazol-2-amine 44 5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -N- [1- (phenylmethyl) -1H-pyrazole- 3-yl] -1,3,4-thiadiazol-2-amine 45 5-{[3- (difluoromethyl) -5-methyl-1H-pyrazol-1-yl] methyl} -N- [1- (phenyl) Methyl) -1H-pyrazole 3-yl] -1,3,4-thiadiazol-2-amine 46 N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5-{[3- (difluoromethyl) -5-methyl-1H-pyrazol-1-yl] methyl} -1,3,4-thiadiazol-2-amine 47 N- {1-[(2,6-dichlorophenyl) methyl] -1H-pyrazole-3- Yl} -5-[(3-nitro-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine 48 N- {1-[(2-chlorophenyl) methyl] -1H- Pyrazol-3-yl} -5-{[5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] methyl} -1,3,4-thiadiazol-2-amine 49 N- {1 -[(2-Chloroph Nyl) methyl] -1H-pyrazol-3-yl} -5-[(3-nitro-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine 50 N- {1- [(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(5-methyl-3-nitro-1H-pyrazol-1-yl) methyl] -1,3, 4-thiadiazol-2-amine 51 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3,5-dimethyl-1H-pyrazole- 1-yl) methyl] -1,3,4-thiadiazol-2-amine 52 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [ (3-Nitro-1H-pyrazo -1-yl) methyl] -1,3,4-thiadiazol-2-amine 53 N- {1-[(2,6-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3 , 5-dimethyl-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine 54 N- {1-[(2,6-dichlorophenyl) methyl] -1H-pyrazole-3- Yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 55 N- {1-[(2-chloro-6-fluoro Phenyl) methyl] -1H-pyrazol-3-yl} -5-{[3- (difluoromethyl) -5-methyl-1H-pyrazol-1-yl] methyl} -1,3,4-thiadiazole-2- Amine 56 N- {1-[( -Chlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine 57 N- {1-[(2,6-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3-methyl-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazole- 2-Amine 58 N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(5-methyl-3-nitro-1H-pyrazol-1-yl) methyl]- 1,3,4-thiadiazol-2-amine 59 N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5-{[3- (trifluoromethyl) -1H-pyrazole -1-I L] methyl} -1,3,4-thiadiazol-2-amine 60 5-[(3-methyl-1H-pyrazol-1-yl) methyl] -N- [1- (phenylmethyl) -1H-pyrazole- 3-yl] -1,3,4-thiadiazol-2-amine 61 N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -5-{[3- (trifluoromethyl) -1H- Pyrazol-1-yl] methyl} -1,3,4-thiadiazol-2-amine 62 5-[(5-methyl-3-nitro-1H-pyrazol-1-yl) methyl] -N- [1- ( Phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazol-2-amine 63 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazole-3- Il} -5-{[3- (Trifluoromethyl) -1H-pyrazol-1-yl] methyl} -1,3,4-thiadiazol-2-amine 64 5-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl]- N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazol-2-amine 65 N- {1-[(2,6-dichlorophenyl) methyl] -1H-pyrazole -3-yl} -5- [1- (5-methyl-3-nitro-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine 66 N- {1-[( 2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1R) -1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3, 4-thiadiazol-2-amine 7 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1S) -1- (3-methyl-1H-pyrazol-1-yl ) Ethyl] -1,3,4-thiadiazol-2-amine
68 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1R) -1- (3,5-dimethyl-1H-pyrazole-1 -Yl) ethyl] -1,3,4-thiadiazol-2-amine 69 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[( 1S) -1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 70 (1S) -1- [5-({1-[( 2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazole-2 -Yl) ethanol 71 (1R) -1- [5-({1- [(2-Chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazole -2-yl) ethanol
72 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (methyloxy) -1- (4-methyl-1,3- Thiazol-2-yl) ethyl] -1,3,4-thiadiazol-2-amine 73 N- {1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [ (Methyloxy) (4-methyl-1,3-thiazol-2-yl) methyl] -1,3,4-thiadiazol-2-amine 74 N- {1-[(2-chloro-6-fluorophenyl) Methyl] -1H-pyrazol-3-yl} -5- [1-methyl-1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazol-2-amine 75 5- [1- (3,5-dimethyl-1H-pi Razol-1-yl) ethyl] -N- {1-[(4-fluorophenyl) methyl] -1H-pyrazol-3-yl} -1,3,4-thiadiazol-2-amine 76 N- {1- [(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazole- 2-Amine 77 5- [1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -N- {1-[(2,3,6-trifluorophenyl) methyl] -1H-pyrazole -3-yl} -1,3,4-thiadiazol-2-amine 78 1- [5-({1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} amino)- 1,3,4-thiadiazol-2-i ] -1- (4-Methyl-1,3-thiazol-2-yl) ethanol 79 1- [5-({1-[(3-chloro-2-fluorophenyl) methyl] -1H-pyrazole-3- Yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol 80 1- [5-({1-[(2, 3-difluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol 81 N- {1-[(2,6-difluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ) Ethyl] -1,3,4-thiadiazole- -Amine 82 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- (1-{[2- (ethyloxy) -3,6-difluorophenyl] methyl} -1H -Pyrazol-3-yl) -1,3,4-thiadiazol-2-amine 83 1- [5-({1-[(2-fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl } Amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol 84 1- [5-({1-[(2,6 -Difluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2- Yl) ethanol 85 N- {1-[(2, -Difluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazole -2-amine 86 N- {1-[(2,6-difluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3
-Methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 87 N- {1-[(3-amino-2,6-difluorophenyl) methyl] -1H-pyrazole -3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 88 1- [5-({1- [(3-Amino-2-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazole -2-yl) ethanol 89 (1S) -1- [5-({1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazole -2-yl] -1- (4-methyl 1,3-thiazol-2-yl) ethanol and 90 (1R) -1- [5-({1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1 3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol,
Or a pharmaceutically acceptable salt thereof.

  In one aspect, the present invention provides a compound selected from:

1 5- [1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -N- (1-{[2- (trifluoromethyl) phenyl] methyl} -1H-pyrazol-3-yl ) -1,3,4-thiadiazol-2-amine 2 N- {1-[(2,5-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl) -1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine
3N- {1-[(2-bromophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1, 3,4-thiadiazol-2-amine 4 N- {1-[(2,5-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazole-1 -Yl) ethyl] -1,3,4-thiadiazol-2-amine 5 N- {1-[(2-bromophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3- Methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 6 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N— {1-[(2-Fluorophenyl) methyl] -1H-pi Razol-3-yl} -1,3,4-thiadiazol-2-amine 7 N- {1-[(3-chloro-2-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [ 1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 8 N- (1-{[2,5-bis (trifluoromethyl) phenyl ] Methyl} -1H-pyrazol-3-yl) -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 9 5- [1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -N- (1-{[5-fluoro-2- (trifluoromethyl) phenyl] methyl} -1H-pyrazole-3- Yl) -1,3,4-thiadiazole- -Amine 10 N- {1-[(2,3-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl ] -1,3,4-thiadiazol-2-amine 11 N- (1-{[2-chloro-5- (trifluoromethyl) phenyl] methyl} -1H-pyrazol-3-yl) -5- [1 -(3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 12 N- {1-[(2,6-difluorophenyl) methyl] -1H- Pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 13 N- {1-[(2 -Fluoro-3-methylphenyl) methyl -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 14 N- {1-[( 3-chloro-2-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazole- 2-Amine 15 N- {1-[(2,3-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 16 N- {1-[(2,3-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (4-methyl-1) , 3-thiazol-2-yl) ethyl] -1 3,4-thiadiazol-2-amine 17 N- {1-[(2-chloro-4-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl- 1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 18 N- {1-[(2-chloro-4-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-Methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 19 N- {1-[(2-chloro-6-fluorophenyl) Methyl] -5-methyl-1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 20 5- [1- (3,5-dimension 1H-pyrazol-1-yl) ethyl] -N- {1-[(2-methylphenyl) methyl] -1H-pyrazol-3-yl} -1,3,4-thiadiazol-2-amine 21 5 -[1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazole-2 -Amine 22 N- {1-[(6-chloro-2-fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazole -1-yl) ethyl] -1,3,4-thiadiazol-2-amine 23 N- {1-[(2-chloro-6-fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl } -5- [1- (3,5-dimethyl) Ru-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 24 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N— {1-[(2-Fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -1,3,4-thiadiazol-2-amine 25 N- {1-[(2-fluoro-3 -Methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazol-2-amine 26 N- {1-[(5-amino-2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazole-2-a 27 N- {1-[(3-amino-2-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) Ethyl] -1,3,4-thiadiazol-2-amine 28 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3 , 5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 29 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazole -3-yl} -5- [1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazol-2-amine 30 1- [5-({1- [(2-Chloro-6-fluorophenyl) methyl] -1 -Pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol 31 N- {1-[(2 -Chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- {1- [4- (trifluoromethyl) -1,3-thiazol-2-yl] ethyl} -1,3 4-thiadiazol-2-amine 32 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(4-methyl-1,3-thiazole -2-yl) methyl] -1,3,4-thiadiazol-2-amine 33 N- {1-[(3-chloro-2-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5 [1- (4-Methyl-1,3-thiazo Ru-2-yl) ethyl] -1,3,4-thiadiazol-2-amine 34 N- {1-[(4-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- ( 3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 35 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl ] -N- (1-{[4- (trifluoromethyl) phenyl] methyl} -1H-pyrazol-3-yl) -1,3,4-thiadiazol-2-amine 36 N- {1-[(2 -Chloro-5-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazole -2-amine and 37 N- {1 [(2-Chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1,3-thiazole- 2-amine,
Or a pharmaceutically acceptable salt thereof.

  In one aspect, the invention provides a compound selected from:

72 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (methyloxy) -1- (4-methyl-1,3- Thiazol-2-yl) ethyl] -1,3,4-thiadiazol-2-amine 73 N- {1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [ (Methyloxy) (4-methyl-1,3-thiazol-2-yl) methyl] -1,3,4-thiadiazol-2-amine 74 N- {1-[(2-chloro-6-fluorophenyl) Methyl] -1H-pyrazol-3-yl} -5- [1-methyl-1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazol-2-amine 75 5- [1- (3,5-dimethyl-1H-pi Razol-1-yl) ethyl] -N- {1-[(4-fluorophenyl) methyl] -1H-pyrazol-3-yl} -1,3,4-thiadiazol-2-amine 76 N- {1- [(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazole- 2-Amine 77 5- [1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -N- {1-[(2,3,6-trifluorophenyl) methyl] -1H-pyrazole -3-yl} -1,3,4-thiadiazol-2-amine 78 1- [5-({1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} amino)- 1,3,4-thiadiazol-2-i ] -1- (4-Methyl-1,3-thiazol-2-yl) ethanol 79 1- [5-({1-[(3-chloro-2-fluorophenyl) methyl] -1H-pyrazole-3- Yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol 80 1- [5-({1-[(2, 3-difluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol 81 N- {1-[(2,6-difluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ) Ethyl] -1,3,4-thiadiazole- -Amine and 82 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- (1-{[2- (ethyloxy) -3,6-difluorophenyl] methyl}- 1H-pyrazol-3-yl) -1,3,4-thiadiazol-2-amine,
Or a pharmaceutically acceptable salt thereof.

  In one aspect, the invention provides a compound selected from:

83 1- [5-({1-[(2-Fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-Methyl-1,3-thiazol-2-yl) ethanol 84 1- [5-({1-[(2,6-difluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} Amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol 85 N- {1-[(2,6-difluoro-3- Methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazol-2-amine 86 N- {1-[(2,6-difluoro-3-methyl) Ruphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 87 N- { 1-[(3-Amino-2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl]- 1,3,4-thiadiazol-2-amine and 88 1- [5-({1-[(3-amino-2-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3 4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol,
Or a pharmaceutically acceptable salt thereof.

  In one aspect, the invention provides a compound selected from:

66 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1R) -1- (3-methyl-1H-pyrazol-1-yl ) Ethyl] -1,3,4-thiadiazol-2-amine 67 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1S) -1- (3-Methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine
68 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1R) -1- (3,5-dimethyl-1H-pyrazole-1 -Yl) ethyl] -1,3,4-thiadiazol-2-amine 69 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[( 1S) -1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 70 (1S) -1- [5-({1-[( 2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazole-2 -Yl) ethanol and 71 (1R) -1- [5- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1, 3-thiazol-2-yl) ethanol,
Or a pharmaceutically acceptable salt thereof.

  In one aspect, the invention provides a compound selected from:

89 (1S) -1- [5-({1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl]- 1- (4-Methyl-1,3-thiazol-2-yl) ethanol and 90 (1R) -1- [5-({1-[(2,6-difluorophenyl) methyl] -1H-pyrazole-3 -Yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol,
Or a pharmaceutically acceptable salt thereof.

  In another aspect, the invention provides the compounds of Examples 66-71, 89, and 90 as a single enantiomer, for example, at least 98% enantiomeric excess (ee).

  In one aspect, the invention provides a compound selected from:

67 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1S) -1- (3-methyl-1H-pyrazol-1-yl ) Ethyl] -1,3,4-thiadiazol-2-amine
69 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1S) -1- (3,5-dimethyl-1H-pyrazole-1 -Yl) ethyl] -1,3,4-thiadiazol-2-amine 70 (1S) -1- [5-({1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazole-3 -Yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol and 89 (1S) -1- [5-({ 1-[(2,6-Difluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazole -2-yl) ethanol,
Or a pharmaceutically acceptable salt thereof.

  In another aspect, compounds that can be used in the present invention include the following compounds:

38 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl]- 1,3,4-thiadiazol-2-amine 39 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3-methyl-1H- Pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine 40 N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- ( 5-methyl-3-nitro-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 41 N- {1-[(2-chlorophenyl) methyl] -1H-pyrazole-3 -Il} -5- {1- [3- (Difluoromethyl) -5-methyl-1H-pyrazol-1-yl] ethyl} -1,3,4-thiadiazol-2-amine 42 N- {1-[(2-chlorophenyl) methyl] -1H-pyrazole- 3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 43 5- {1- [3- (difluoromethyl) -5-methyl-1H-pyrazol-1-yl] ethyl} -N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazol-2-amine 44 5- [ 1- (3-Methyl-1H-pyrazol-1-yl) ethyl] -N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazol-2-amine 45 5 -{[3- (Gif Fluoromethyl) -5-methyl-1H-pyrazol-1-yl] methyl} -N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazol-2-amine 46 N -{1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5-{[3- (difluoromethyl) -5-methyl-1H-pyrazol-1-yl] methyl} -1, 3,4-thiadiazol-2-amine 47 N- {1-[(2,6-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3-nitro-1H-pyrazol-1-yl ) Methyl] -1,3,4-thiadiazol-2-amine 48 N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5-{[5-methyl-3- ( Trifluoromethyl ) -1H-pyrazol-1-yl] methyl} -1,3,4-thiadiazol-2-amine 49 N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5 [(3-Nitro-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine 50 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H- Pyrazol-3-yl} -5-[(5-methyl-3-nitro-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine 51 N- {1-[(2 -Chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazole-2 -Amine 52 N- {1- (2-Chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3-nitro-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazole-2 -Amine 53 N- {1-[(2,6-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1 3,4-thiadiazol-2-amine 54 N- {1-[(2,6-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazole- 1-yl) ethyl] -1,3,4-thiadiazol-2-amine 55 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- { [3- (Difluoromethyl ) -5-methyl-1H-pyrazol-1-yl] methyl} -1,3,4-thiadiazol-2-amine 56 N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl } -5-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine 57 N- {1-[(2,6-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3-methyl-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine 58 N- {1-[(2- Chlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(5-methyl-3-nitro-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine 59 N -{1-[(2- Rophenyl) methyl] -1H-pyrazol-3-yl} -5-{[3- (trifluoromethyl) -1H-pyrazol-1-yl] methyl} -1,3,4-thiadiazol-2-amine 60 5 -[(3-Methyl-1H-pyrazol-1-yl) methyl] -N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazol-2-amine 61 N -[1- (Phenylmethyl) -1H-pyrazol-3-yl] -5-{[3- (trifluoromethyl) -1H-pyrazol-1-yl] methyl} -1,3,4-thiadiazole-2 -Amine 62 5-[(5-Methyl-3-nitro-1H-pyrazol-1-yl) methyl] -N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1,3,4 -Thiadiazole-2 -Amine 63 N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-{[3- (trifluoromethyl) -1H-pyrazol-1-yl ] Methyl} -1,3,4-thiadiazol-2-amine 64 5-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -N- [1- (phenylmethyl) -1H-pyrazole -3-yl] -1,3,4-thiadiazol-2-amine and 65 N- {1-[(2,6-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- ( 5-methyl-3-nitro-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine,
Or a pharmaceutically acceptable salt thereof.

In another aspect, compounds of formula (X) can be used in the present invention.

In the formula:
X is N and Y is CR ⁵ ; or X is C and Y is S;
Z is selected from N and CH;
R ¹ is selected from H and Me;
R ² is selected from H, OH, OMe and Me;
One R ³ group is NHR ^A and the remaining R ³ groups are independently selected from C _1-3 alkyl, F, Cl, Br, CF ₃ and NHR ^A ;
R ⁴ is selected from Me, CF ₃ , NO ₂ and CHF ₂ ;
R ⁵ is selected from H, Me and CHF ₂ ;
R ⁶ is selected from H and Me;
Each R ^A is independently selected from —C (O) C _1-4 alkyl or —C (O) OC _1-4 alkyl;
p is 0-3.

In another aspect, compounds that can be used in the present invention include:
A ethyl (2-fluoro-3-{[3-({5- [1-hydroxy-1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazole- 2-yl} amino) -1H-pyrazol-1-yl] methyl} phenyl) carbamate and BN- (3-{[3-({5- [1- (3,5-dimethyl-1H-pyrazol-1) -Yl) ethyl] -1,3,4-thiadiazol-2-yl} amino) -1H-pyrazol-1-yl] methyl} -2,4-difluorophenyl) acetamide,
Or a pharmaceutically acceptable salt thereof.

In one aspect, the invention provides a process for preparing a compound of formula (Ia)
Where
X is N and Y is CR ⁵ ; or X is C and Y is S;
R ¹ is selected from H and Me;
R ² is selected from H, OH, OMe and Me;
Each R ³ is independently selected from C _1-3 alkyl, F, Cl, Br, CF ₃ and NH ₂ ;
R ⁴ is selected from Me, CF ₃ , NO ₂ and CHF ₂ ;
R ⁵ is selected from H, Me and CHF ₂ ;
R ⁶ is selected from H and Me; and p is 0-3;
This process includes reacting a compound of formula (II) with a compound of formula (III).

In another embodiment, the compound of formula (II) is reacted with a compound of formula (III) in a suitable solvent such as DCM or ethanol. In another aspect, the process for preparing a compound of formula (Ia) comprises hydrazine carbothioamide intermediate prepared from reaction of a compound of formula (II) with a compound of formula (III) and dehydration such as H ₂ SO ₄ or POCl _3. Reacting with reagents.

In one aspect, the present invention provides a process for the preparation of a compound of formula (Ib)
Where
X is N and Y is CR ⁵ ; or X is C and Y is S;
R ¹ is selected from H and Me;
R ² is selected from H, OH, OMe and Me;
Each R ³ is independently selected from C _1-3 alkyl, F, Cl, Br, CF ₃ and NH ₂ ;
R ⁴ is selected from Me, CF ₃ , NO ₂ and CHF ₂ ;
R ⁵ is selected from H, Me and CHF ₂ ;
R ⁶ is selected from H and Me; and p is 0-3;
The process also includes reacting the compound of formula (IIb) with the compound of formula (IIIb).

In another embodiment, the compound of formula (IIb) is reacted with a compound of formula (IIIb) in the presence of a base, for example a non-nucleophilic hindered base such as ^t BuONa or ^t BuOK.

Terms and Definitions As used herein, the term “(C _1-3 ) alkyl” refers to a straight or branched chain alkyl group having 1 to 3 carbon atoms. Examples of the (C _1-3 ) alkyl group include methyl (Me), ethyl (Et), n-propyl and isopropyl.

As used herein, the term “(C _1-4 ) alkyl” refers to a straight or branched alkyl group having 1 to 4 carbon atoms. Examples of (C _1-4 ) alkyl groups include methyl (Me), ethyl (Et), propyl (Pr) (eg, n-propyl, isopropyl), butyl (Bu) (eg, n-butyl, sec- Butyl, isobutyl, tert-butyl (t-Bu)).

  As used herein, the term “halo” refers to fluoro, chloro, bromo and iodo groups. In one embodiment, the term “halo” as used herein refers to fluoro, chloro and bromo groups. In another embodiment, the term “halo” as used herein refers to chloro, bromo and iodo groups.

As used herein, the term “C _1-3 alkoxy” refers to a straight or branched alkoxy group having 1 to 3 carbon atoms. Examples of the C _1-3 alkoxy group include methoxy, ethoxy, propoxy and isopropoxy.

  As used herein, the term “compound of the invention” means a compound of formula (I) or a pharmaceutically acceptable salt thereof. The term “a compound of the invention” means any of the compounds of the invention as defined above.

  Furthermore, phrases such as “a compound of formula (I) or a pharmaceutically acceptable salt thereof” or “a compound of the invention” refer to a compound of formula (I) or a pharmaceutically acceptable compound of formula (I). It is understood that it is intended to encompass possible salts or solvates, or pharmaceutically acceptable combinations thereof. Thus, as a non-limiting example used for purposes of illustration, “a compound of formula (I) or a pharmaceutically acceptable salt thereof” is a pharmaceutically acceptable salt of a compound of formula (I) that exists as a solvate. An acceptable salt is included or the phrase may include a mixture of a compound of formula (I) and a salt of the compound of formula (I).

Those skilled in the art will recognize that certain compounds of the invention can form pharmaceutically acceptable salts with acids or bases, while other particular compounds of the invention cannot readily form such salts. Will be understood. It will be understood that all possible pharmaceutically acceptable salts of the compounds of formula (I) are intended to be included within the scope of the present invention.
It will be further understood that all crystal forms, polymorphs and enantiomers of the compounds of the invention, or mixtures thereof, are intended to be included within the scope of the invention. Unless otherwise limited (eg, where absolute stereochemistry is indicated), the compounds of the invention having at least one stereocenter and thus forming enantiomers (eg, R ¹ and R ² are For example, when R ¹ is defined for formula (I) and R ² represents hydroxy (OH)), the compound is an enantiomer, eg a 1: 1 mixture of enantiomers, That is, an enantiomeric racemic mixture may be included. These can be separated using conventional techniques such as chiral HPLC. In one embodiment, relative to an isomer of a compound of the present invention in which absolute stereochemistry is specified or otherwise described as a single enantiomer, the isomer of the compound of the present invention is at least 80% e. e. Have In another embodiment, the isomer of the compound of the invention has 90% e.e. e. E.g., at least 95% e.e. e. Have In another embodiment, the isomer of the compound of the invention has at least 98% e.e. e. E.g., at least 99% e.e. e. It corresponds to.

  Some of the compounds of the present invention may be crystallized or recrystallized from solvents such as aqueous and organic solvents. In such cases, solvates can be formed. The scope of the present invention includes hydrates containing various amounts of water generated in processes such as lyophilization and stoichiometric solvates containing compounds.

  Since the compounds of formula (I) are intended for use in pharmaceutical compositions, in certain embodiments they are in substantially pure form, such as at least 60% pure, more preferably at least 75% pure and especially It will be readily appreciated that it is provided at least 85% pure, especially at least 98% pure (where% is on an equal weight basis). Impure preparations of the compounds may be used for the preparation of the more pure forms used for pharmaceutical compositions. Impure preparations of said compounds are at least 1%, more preferably at least 5%, and more particularly 10% to 59% of a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or Solvates should be included.

Compound Preparation The general processes used to synthesize compounds of formula (I) are described in Reaction Schemes 1-13 and illustrated in the examples.

Preparation of a compound of formula (I) A compound of formula (Ia), which is a thiadiazole compound of formula (I) when Z is N, isothiocyanate (p, R ³ and R ⁶ of formula (II) Hydrazine carbothioamide intermediate (isolated and purified directly or directly without purification) of hydrazide of formula (III) (same as I)) and hydrazide of formula (III) (R ¹ , R ² and R ⁴ are the same as formula (I)) It can be prepared according to scheme 1 by reaction via) used in the next step.

Compounds of formula (Ib) which are thiazole compounds of formula (I) when Z is CH are amides of formula (IIb) (p, R ³ and R ⁶ are the same as in formula (I)) and formula (IIIb) Can be prepared according to Scheme 2 by the reaction of Nalogenated thiazole (R ¹ , R ² and R ⁴ are each the same as in formula (I)).

For compounds of formula (I) where at least one R ³ group is NH ₂ , the reaction of Scheme 1 or Scheme 2 yields compounds of formula (X) above, such as amides or carbamates, for example It can be carried out with the NH ₂ group protected in the form of a suitable protecting group. This protecting group can then be removed under standard conditions to give the compound of formula (I).

Synthesis of the isothiocyanate intermediate of formula (II) The isothiocyanate intermediate of formula (II) (p, R ³ and R ⁶ are the same as in formula (I)) can be synthesized as shown in Scheme 3 And a 3-aminopyrazole intermediate of formula (IV) (p, R ³ and R ⁶ are the same as in formula (I)).

The 3-aminopyrazole intermediate of formula (IV) is a protected intermediate of formula (V) (p, R ³ and R ⁶ are the same as in formula (I)), as shown in Schemes 4 and 5, respectively, or It can be prepared from an intermediate of formula (VI) (p, R ³ and R ⁶ are the same as in formula (I)).

The protected 3-aminopyrazole compound of formula (V) is a 3-acetylaminopyrazole compound of formula (VII) (R ⁶ is the same as formula (I)) and a benzyl bromide compound or benzyl as shown in Scheme 6 It can be prepared by reaction between methyl sulfonate (mesylate or OMs) compounds (p and R ³ are the same as in formula (I)).

The protected 3-aminopyrazole intermediate of formula (VI) can be converted to an N-phthalimide intermediate of formula (VIII) (R ⁶ is the same as formula (I)) and benzyl bromide or benzyl It can be prepared by reacting a Lato compound (p and R ³ are the same as in formula (I)).

Benzyl bromide compounds that are not commercially available, or benzyl mesylate compounds (one R ³ group is a protected amine, such as Boc-protected amine, ethyloxycarbonyl-protected amine, or acetyl-protected amine) are shown in Scheme 8. Can be prepared. In each case, the amine protecting group is removed at a suitable stage in the preparation of the compound of formula (I) to give a compound of formula (I) in which one R ³ group is NH ₂ .

The protected 3-aminopyrazole intermediate of formula (VII) and formula (VIII) is prepared from commercially available 3-aminopyrazole (R ⁶ is the same as formula (I)) as shown in Schemes 9 and 10 be able to.

Synthesis of hydrazine intermediate of formula (III) The hydrazine intermediate of formula (III) (R ¹ , R ² and R ⁴ are the same as in formula (I)), as shown in Scheme 11, IX) N-alkylpyrazole intermediates (R ¹ , R ² and R ⁴ are the same as in formula (I) and R ⁷ is (C _1-4 ) alkyl).

N-alkylpyrazole compound of formula (IX) (X is N and Y is CR ⁵ , R ¹ and R ⁴ are the same as in formula (I), R ² is H or Me, R ⁷ Is a (C _1-4 ) alkyl) compound of formula (IXa), as shown in Scheme 12, commercially available alkyl bromides (R ¹ and R ² are the same as in formula (I) and R ⁷ is (C _{1 -4} ) alkyl). 2-alkyl 1,3 thiazole compounds of formula (IX) (X is C and Y are S, R ¹ , R ² and R ⁴ are the same as in formula (I) and R ⁷ is (C _1-4 ) alkyl The compound of formula (IXb) is a starting from a commercially available nitrile compound (R ¹ and R ² are the same as formula (I) and R ⁷ is (C _1-4 ) alkyl) as shown in Scheme 13. And can be prepared via a thioamide intermediate compound.

A compound of formula (IXb (i)), which is a compound of formula (IXb), where R ¹ is Me and R ² is OH, is a compound of formula (IXb), wherein R ¹ is Me and R ² is H ) Can be prepared from compounds of formula (IXb (ii)).

For compound (IXb (ii)) (R ¹ is Me and R ² is H), this compound undergoes slow autoxidation to give compound (IXb (i)) (R ¹ is Me and R ² Note that becomes OH). Therefore, to minimize autooxidation, compound (IXb (ii)) is best used in the next reaction step (Scheme 11) as soon as the synthesis is complete.

  One skilled in the art may need and / or desire to protect one or more sensitive groups in a molecule or suitable intermediate that prevents undesired side reactions in the preparation of compounds of formula (I). Will be understood. Suitable protecting groups for use in the present invention are known to those skilled in the art and may be used in a conventional manner. For example, “Protective groups in organic synthesis” by T.M. W. Greene and P.M. G. M.M. Wuts (John Wiley & sons 1991) or “Protecting Groups” by P.M. J. et al. See Kocienski (Georg Thime Verlag 1994). Examples of suitable amino protecting groups are acyl-type protecting groups (eg formyl, trifluoroacetyl, acetyl), aromatic urethane-type protecting groups (eg benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protection Groups (eg 9-fluorenylmethoxycarbonyl (Fmoc), N-tert-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl, ethyloxycarbonyl) and alkyl or aralkyl type protecting groups (eg benzyl , Trityl, chlorotrityl). Examples of suitable oxygen protecting groups include, for example, alkylsilyl groups such as trimethylsilyl or tert-butyldimethylsilyl, alkyl ethers such as tetrahydropyranyl or tert-butyl, or esters such as acetate.

  It will be readily apparent to one skilled in the art that other compounds of formula (I) can be prepared using methods similar to those described above or with reference to the experimental procedures of the examples described herein. It will be obvious. Further details of the preparation of compounds of formula (I) are described in the examples.

Compositions and Formulations The compounds of the present invention may be formulated for administration in a manner convenient for use in human or veterinary medicine by analogy with antimicrobial drug formulations or other antitubercular drug formulations.

  Prior to administration to a patient, the compounds of the invention are generally, but not necessarily, formulated into pharmaceutical compositions. In one aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents. . The carrier, excipient or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to these recipients.

  A therapeutically effective amount of a compound of the present invention can be determined by methods known in the art. The therapeutically effective amount depends on the patient's age and general physiological conditions, route of administration and the pharmaceutical formulation used. The therapeutic amount is usually between about 1 and 2000 mg / day. The daily dose adopted for the treatment of acute or chronic humans is in the range of 0.01 to 250 mg / kg body weight. For example, the daily dose is administered 1 to 4 times the daily dose depending on the route of administration and medical condition of the patient. May be. When the composition is comprised of dosage units, each dosage unit will contain 1 mg to 2 g of active ingredient.

  The invention further relates to a pharmaceutical composition for the treatment of tuberculosis comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention still further provides: a) 1-2000 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and b) 0.1-2 g of one or more pharmaceutically acceptable doses. It relates to a pharmaceutical composition comprising a dosage form.
The pharmaceutical composition of the present invention can be used for the treatment of tuberculosis in mammals including humans, including oral dosage forms and parenterals.

  The pharmaceutical composition of the present invention includes a dosage form adapted for oral or parenteral administration of mammals including human.

  The composition may be formulated for administration by any convenient route. For the treatment of tuberculosis, the composition may be in the form of tablets, capsules, powders, granules, lozenges, aerosols or liquid formulations such as oral or sterile parenteral solutions or suspensions.

  Oral tablets and capsules may be in unit dose presentation form, and conventional excipients such as syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone, lactose, sugar, corn starch Contains fillers such as calcium phosphate, sorbitol or glycine, tableting lubricants such as magnesium stearate, talc, polyethylene glycol or silica, disintegrants such as potato starch, or acceptable wetting agents such as sodium lauryl sulfate It's okay. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be reconstituted with water or other appropriate vehicle prior to use. May be provided as a dry product. Such oral liquid formulations are suspensions of emulsifiers such as sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat, lecithin, sorbitan monooleate, or acacia Conventional additives such as edible agents, oily esters such as almond oil, glycerol, glycerin, non-aqueous vehicles such as propylene glycol or ethyl alcohol (which may include edible oils), methyl or propyl p-hydroxybenzoic acid or sorbine It may contain preservatives such as acids and, if desired, conventional flavoring or coloring agents.

  For parenteral administration, fluid unit dosage forms are prepared using the compound and a sterile vehicle, preferably water. The compound may be suspended or dissolved in the vehicle depending on the vehicle and concentration used. In preparing solutions, the compound may be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.

  In some embodiments of the invention, drugs such as local anesthetics, preservatives, buffering agents and the like are dissolved in the vehicle. To increase stability, the composition may be frozen after filling into the vial to remove moisture under vacuum. The lyophilized powder may then be sealed in a vial and supplied with a vial containing water for injection to dissolve before use. In the case of parenteral suspensions, they are prepared in substantially the same manner except that the compound is suspended instead of being dissolved in the vehicle and that sterilization cannot be achieved by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. It is preferred to include a surfactant or wetting agent in the composition to facilitate uniform distribution of the compound.

  The compound of formula (I) or a pharmaceutically acceptable salt thereof may be a single therapeutic agent in the composition of the invention and may be combined with one or more additional therapeutic agents in the formulation. May be put in.

  Accordingly, in a further aspect, the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. Examples of one or more such additional therapeutic agents include, but are not limited to, anti-tuberculosis drugs, including but not limited to amikacin, aminosalicylic acid, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, Examples include pyrazinamide, rifamycin (rifampin, rifapentine and rifabutin, etc.), streptomycin, clarithromycin, azithromycin, oxazolidinone and fluoroquinolones (ofloxacin, ciprofloxacin, moxifloxacin, and gatifloxacin, etc.). Such chemotherapy is determined by the judgment of the treating physician using the preferred combination of drugs. “First-line” chemotherapeutic drugs used to treat M. tuberculosis infections that are not drug resistant include isoniazid, rifampin, ethambutol, streptomycin and pyrazinamide. "Second line" chemotherapeutic drugs used to treat M. tuberculosis infection that is resistant to one or more "first line" drugs include ofloxacin, ciprofloxacin, ethionamide, aminosalicylic acid, cycloserine, amikacin , Kanamycin and capreomycin. In addition to the foregoing, there are a number of new anti-tuberculosis drugs derived from clinical trials that can be employed as one or more additional therapeutic agents in combination with a compound of formula (I). These include, but are not limited to, TMC-207, OPC-67683, PA-824, LL-3858 and SQ-109.

In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and an antituberculosis drug, in particular isoniazid (INH), rifampin, pyrazinamide and ethambutol and / or an antibacterial or anti-AIDS drug. A combination comprising one or more additional therapeutic agents.
In a further aspect, the one or more additional therapeutic agents are, for example, reagents useful for treating tuberculosis in mammals, therapeutic vaccine agents, antibacterial agents, antiviral agents; antibiotics and / or HIV / AIDS therapeutic agents. . Examples of such therapeutic agents include isoniazid (INH), ethambutol, rifampin, pyrazinamide, streptomycin, capreomycin, ciprofloxacin and clofazimine.

  In one aspect, the one or more additional therapeutic agents are therapeutic vaccines. Thus, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered in conjunction with vaccination against mycobacterial infections, in particular vaccination against Mycobacterium tuberculosis infection. Existing vaccines against mycobacterial infections include Calmette Guerin (BCG). A modified BCG strain that recombinantly expresses additional antigens, cytokines and other drugs to improve efficacy and safety of vaccines currently being developed for the treatment, prevention or improvement of mycobacterial infections; And attenuated mycobacteria expressing various antigens similar to Mycobacterium tuberculosis from BCG; and subunit vaccines. The subunit vaccine may be administered in the form of one or more individual protein antigens, in the form of a fusion or a fusion of multiple protein antigens, optionally supplemented to either of these Or a form of a polynucleotide encoding one or more individual protein antigens, or a fusion or of multiple protein antigens, such as when inserted into an expression vector and the polynucleotide is administered. Administration may be in the form of a polynucleotide encoding the fusion. Examples of subunit vaccines include, but are not limited to, fusion proteins from M72, ie, Mtb32a and Mtb39 antigens; HyVac-1, ie, fusion proteins from antigen 85b and ESAT-6; HyVac-4, Fusion protein from antigen 85b and Tb10.4; fusion from MVA85a, denatured vaccinia virus Ankara expressing antigen 85a; and Aeros-402, ie antigen 85a, antigen 85b and Tb10.4 Adenovirus 35 expressing body protein.

  A compound of formula (I), or a pharmaceutically acceptable salt thereof, can be obtained by administering a compound of the invention and a vaccine together in the same dosage form, or a compound of the invention and a vaccine in different dosage forms simultaneously. By administration, i) may be administered to individuals previously vaccinated against mycobacterial infections; ii) may be subsequently administered to individuals vaccinated against subsequent mycobacterial infections; or iii) mycobacteria It may be co-administered with a vaccine against infection.

  When a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with one or more therapeutic agents, the dosage of the compound or agent is such that the compound or agent is used alone It may be different from the case. Appropriate doses will be readily appreciated by those skilled in the art. The amount of the compound of the present invention and the therapeutic agent (s) required for use in treatment will depend on the nature of the disease, age and the disease of the patient and will ultimately be at the discretion of the attending physician or veterinarian. Will be understood.

  The combination may be provided for use in the form of a pharmaceutical formulation. In a further aspect of the invention, a pharmaceutical combination comprising a compound of formula (I), or a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents, and one Or a plurality of pharmaceutically acceptable carriers, excipients or diluents. The individual components of such a combination may be administered sequentially or simultaneously by any convenient route in separate or combined pharmaceutical formulations.

  Where administration is continuous, either the compound of the invention or one or more therapeutic agents may be administered first. If administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition. It will be appreciated that when combined in the same formulation, the compound and drug must be stable, compatible with each other and with other components of the formulation. When formulated separately, such compounds may be provided in a suitable formulation in a manner known in the art.

Abbreviations In the description of the present invention, chemical elements are identified by the periodic table of elements. Abbreviations and symbols herein follow the normal use of abbreviations and symbols by those skilled in the art. The following abbreviations are used herein.

EtOAc ethyl acetate Ac acetyl AcOH acetic acid Ac ₂ O acetic anhydride anh anhydrous Boc N-tert-butoxycarbonyl Boc anhydride di-tert-butyl Celite® dicarbonate carbonate-filtered diatomaceous silica
(Trademark of Manville Corp., Denver, Colorado)
DME dimethoxyethane DCM dichloromethane DIBAL-H diisobutylaluminum hydride DMF dimethylformamide DMSO-d6 deuterated dimethyl sulfoxide DMSO dimethyl sulfoxide ES MS electrospray mass spectrometry Et ethyl EtOH ethanol h time HPLC high performance liquid chromatography int. Intermediate LCMS Liquid Chromatography Mass Spectrometry Mesylate Methyl sulfonic acid Me Methyl MeOH Methanol Ms Methyl sulfonic acid min (s) Min NaBH (OAc) 3 Sodium triacetoxyborohydride NMR Nuclear magnetic resonance spectroscopy Rt Retention time t-BuOMe Methyl t -Butyl ether t-Buo tert-butyloxy TFA trifluoroacetic acid THF tetrahydrofuran uv UV.

(Example)
The following examples illustrate the invention. These examples do not limit the scope of the invention, but rather are intended to provide one of ordinary skill in the art with guidance for preparing and using the compounds, compositions, and methods of the invention. While detailed embodiments of the present invention have been described, it will be appreciated by those skilled in the art that various changes and modifications can be made. References to preparations made by methods similar to other preparations or other general methods of preparation may include variations in normal parameters such as time, temperature, experimental conditions, minor changes in reagent amounts, etc. .

Proton nuclear magnetic resonance ( ¹ H NMR) spectra were recorded, and the chemical shift (δ) from the internal standard tetramethylsilane (TMS) was recorded in a low magnetic field in parts per million. Abbreviations in NMR data are: s = single line, d = double line, t = triple line, q = quadruple line, m = multiple line, dd = double line double line, dt = triple line The double line of the line, app = apparent, br = broad. Mass spectra were obtained using electrospray (ES) ionization technology. Record all temperatures in degrees Celsius.

  Unless otherwise specified, reactions involving metal hydrides including lithium hydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium hydride, sodium borohydride, sodium triacetoxyborohydride under argon or nitrogen atmosphere It carried out in.

Preparation of Intermediate <br/> Intermediate 1: N-1H-pyrazol-3-yl acetamide

1H-pyrazol-3-amine (ALDRICH, 11.32 g, 0.136 mol) was dissolved in 100 mL of distilled water. NaHCO ₃ (34 g, 0.408 mol) was added slowly. Next, acetic anhydride (27.55 g, 0.272 mol) was added dropwise, and the resulting suspension was heated to reflux overnight. The mixture was cooled to room temperature, and the resulting solid was filtered off and confirmed as the title compound (8.4 g, 0.067 mol, 49%). After concentration of the filtrate, a second precipitate was obtained (2.7 g, 0.021 mol, 16%) which was also confirmed as the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 12.23 (brs, 1H), 10.30 (brs, 1H), 7.55 (brs, 1H), 6.45 (brs, 1H), 1.97 (s, 3H). [ES + MS] m / z 126 (MH ^<+> ).

Intermediate 2: 1,1-dimethylethyl [4-chloro-3- (hydroxymethyl) phenyl] carbamate

Sodium carbonate previously dissolved in 4 mL water in a solution of (5-amino-2-chlorophenyl) methanol (Aldrich, 500 mg, 3.17 mmol) in a mixture of dioxane (7.5 mL), water (7.5 mL) (336 mg, 3.17 mmol) was added. The solution was stirred and cooled in an ice bath. Boc anhydride (Aldrich, 692 mg, 3.17 mmol) was added in one portion and stirring was continued at room temperature for 3 hours. Dioxane was removed under reduced pressure and the aqueous layer was cooled, then covered with a layer of ethyl acetate and acidified to pH 4 with dilute KHSO ₄ (10%, aq) (ALDRICH). It was then extracted (EtOAc) and purified on a chromatography column 25 g cartridge (ISOLUTE silicon) using Hex / EtOAc 100/0 → 50/50 to give 1,1-dimethylethyl [4-chloro-3- (hydroxy Methyl) phenyl] carbamate (560 mg, 2.17 mmol, 68%) was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.46 (brs, 1H), 7.72 (s, 1H), 7.21-7.32 (m, 2H), 5.35 (t 1H), 4.48 (d, 2H), 1.47 (s, 9H).

Intermediate 3: 1,1-dimethylethyl [3- (hydroxymethyl) -2-methylphenyl] carbamate

The title compound was prepared according to the procedure for Intermediate 2 above. (3-Amino-2-methylphenyl) methanol (Aldrich, 300 mg, 2.18 mmol) and Boc anhydride (Aldrich, 716 mg, 3.28 mmol) were used as starting reaction materials. 1,1-Dimethylethyl [3- (hydroxymethyl) -2-methylphenyl] carbamate (452 mg, 1.905 mmol, 87%) was obtained as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 8.53 (brs, 1H), 7.06-7.17 (m, 3H), 5.06 (t, 1H), 4.46 (d 2H), 2.07 (s, 3H), 1.44 (s, 9H).
Intermediate 4: 1,1-dimethylethyl [3- (bromomethyl) -4-chlorophenyl] carbamate

To a solution of Intermediate 2 (200 mg, 0.776 mmol) in DCM (5 mL) was added triphenylphospin (Aldrich, 244 mg, 0.931 mmol) and carbon tetrabromide (Aldrich, 386 mg, 1.164 mmol) in an ice-water bath. Added at. After 15 minutes, the reaction mixture was stirred at room temperature for 15 minutes and the reaction mixture was checked by TLC (Hex: EtOAc) (1: 1) and LCMS to check for reaction completion. The solvent was evaporated under vacuum. The residue was purified on a chromatography column 10 gr cartridge (ISOLUTE silica) using Hex / EtOAc 100/0 → 0/100. 1,1-Dimethylethyl [3- (bromomethyl) -4-chlorophenyl] carbamate (206 mg, 0.643 mmol, 83%) was obtained as a pale yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.58 (br.s, 1H), 7.77 (br.s, 1H), 7.35 (m, 2H), 4.67 (s, 2H), 1.48 (s, 9H).

Intermediate 5: 1, 1-dimethylethyl [3- (bromomethyl) -2-methylphenyl] carbamate

The title compound was prepared according to the procedure for Intermediate 4 above. Intermediate 3 (443 mg, 1.86 mmol), triphenylphospin (Aldrich, 588 mg, 2.24 mmol) and carbon tetrabromide (Aldrich, 929 mg, 2.80 mmol) were used as starting reaction materials. The title compound (293 mg, 0.976 mmol, 52%) was obtained as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 8.64 (br.s, 1H), 7.20-7.27 (m, 2H), 7.09-7.15 (m, 1H) 4.73-4.79 (m, 2H), 2.19-2. 21 (m, 3H), 1.45 (s, 9H).

Intermediate 6: N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} acetamide

To a solution of intermediate 1 (3 g, 24 mmol) in anhydrous DMF (40 mL) at 0 ° C. was added sodium hydride (0.63 g, 26.4 mmol) and the mixture was stirred at ice-cold temperature for 30 minutes. To this solution, 2- (bromomethyl) -1-chloro-3-fluorobenzene (Aldrich, 5.36 g, 24 mmol) was added dropwise over 30 minutes and then stirred at ice-cooled temperature for an additional 30 minutes. The reaction was quenched by adding water (1 mL). The resulting solution was diluted with EtOAc (150 mL) and washed with saturated NH ₄ Cl (3 × 60 mL). The organic fraction was dried over Na ₂ SO ₄ and concentrated to dryness. N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} acetamide (4.12 g) by silica column chromatography (100% Hex → 100% EtOAc, 100 g, 30 min) 64.2%). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.71 (s, 1H), 7.05-7.36 (m, 4H), 6.65 (d, 1H), 5.34 (d, 2H ), 210 (s, 3H) [ES + MS] m / z: 268 (MH +).

  Intermediates 7-25 were prepared by a method similar to that described for Intermediate 6 except that benzyl bromide (2- (bromomethyl) -1-chloro-3-fluorobenzene) was replaced with that in Table A. did.

Intermediate 20: N- {1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} acetamide

Intermediate 1 (300 mg; 2.398 mmol) is dissolved in 3 mL anhydrous DMF at 0 ° C., then NaH (96 mg, 2.4 mmol) is added and the reaction mixture is stirred for 20 minutes under the same temperature conditions, after which 2,6-Difluorobenzyl bromide (496 mg, 2.4 mmol) dissolved in 2 ml of anhydrous DMF was added dropwise. The reaction was left under the same conditions for 20 hours until it reached room temperature. The reaction mixture was then diluted with AcOEt and NH ₄ Cl. The phases were separated and the organic phase was washed with brine. The organic phase was dried over MgSO ₄ , filtered and concentrated to dryness under vacuum. The crude was purified by silica gel chromatography using a Hex / EtOAc gradient (0% -70%). The relevant fractions were combined and evaporated to dryness to give the title compound as a white solid (377 mg; 63%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.39 (brs, 1H), 7.66 (d, 1H), 7.39-7.49 (m, 1H), 7.07-7 .15 (m, 2H), 6.43 (d, 1H), 5.25 (s, 2H), 1.91 (s, 3H). [ES + MS] m / z 252 (MH ^<+> ).

Method B
Intermediate 26: N- {1-[(2-fluorophenyl) methyl] -1H-pyrazol-3-yl} acetamide

To a solution of intermediate 1 (200 mg, 1.598 mmol) in ACN (10 mL) under N ₂ (g) atmosphere, K ₂ CO ₃ (Aldrich, 331 mg, 2.398 mmol) and 1- (bromomethyl) -2-fluorobenzene (Aldrich, 302 mg, 1.598 mmol) was added. The reaction mixture was stirred and heated to reflux for 1 hour. The solvent was removed and the crude was partitioned between EtOAc and brine, the organic layer was dried over MgSO ₄ (anhydrous) and then filtered. EtOAc was evaporated under vacuum. The residue was purified on Si (II) chromatography cartridge using Hex: EtOAc mixture as eluent to give the title compound (123 mg, 0.527 mmol, 33%). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.72 (br, s, 1H), 7.33-7.37 (m, 3H), 7.17-7.20 (m, 2H), 6 .70 (d, 1H), 5.18 (s, 2H), 2.13 (s, 3H). [ES + MS] m / z 234 (MH ^<+> ).

Intermediate 27: 2- (1H-pyrazol-3-yl) -1H-isoindole-1,3 (2H) -dione

In a 500 mL round bottom flask, a solution of a mixture of 3-aminopyrazole (Aldrich, 10 g, 120 mmol) and phthalic anhydride (Aldrich, 24.96 g, 168 mmol) in 1,4-dioxane (150 mL) was refluxed for 17 hours. Stir. The reaction was brought to room temperature and the solvent was evaporated to dryness. The residue was washed with EtOH and the yellow solid was filtered to give 23.6 g (92% yield) of the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 13.09 (brs, 1H), 7.89-7.98 (m, 4H), 7.86 (brs, 1H), 6.36 (d 1H). [ES + MS] m / z 214 (MH ^<+> ).

Intermediate 28: 2- (5-Methyl-1H-pyrazol-3-yl) -1H-isoindole-1,3 (2H) -dione

In a 100 mL round bottom flask, 1,4- The solution in dioxane (30 mL) was stirred at reflux for 25 hours. The reaction was brought to room temperature and the resulting precipitate was filtered and washed with EtOH to give 589 mg of the title compound as a yellow solid. The filtrate was evaporated to dryness and an additional batch of 331 mg was obtained after washing the residue with EtOH (overall yield: 79%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 12.77 (brs, 1H), 7.87-7.98 (m, 4H), 6.09 (s, 1H), 2.28 (s 3H). [ES + MS] m / z 228 (MH ^<+> ).

Intermediate 29: 2- {1-[(3-chloro-2-fluorophenyl) methyl] -1H-pyrazol-3-yl} -1H-isoindole-1,3 (2H) -dione

In a 100 mL round bottom flask, intermediate 27 (2- (1H-pyrazol-3-yl) -1H-isoindole-1,3 (2H) -dione, 500 mg, 2.345 mmol), 1- (bromomethyl)- A solution of 3-chloro-2-fluoro-benzene (ALFAAESAR, 629 mg, 2.81 mmol) and potassium carbonate (ALDRICH) (389 mg, 2.81 mmol) in acetonitrile (20 mL) was stirred at reflux for 4 hours. An additional 0.5 equivalent (262 mg) of 1- (bromomethyl) -3-chloro-2-fluoro-benzene (ALFAAESAR) was added and the reaction was stirred at reflux for 20 hours. The reaction was allowed to return to room temperature, potassium carbonate was filtered off and washed with DCM. The filtrate was evaporated to dryness to give 887 mg of crude, which was purified by silica gel chromatography using an ethyl acetate / hexane gradient (8% → 70%) to give unnecessary 2- {1-[(3- Chloro-2-fluorophenyl) methyl] -1H-pyrazol-5-yl} -1H-isoindole-1,3 (2H) -dione isomer was isolated. 452 mg (yield: 54%) of 2- {1-[(3-chloro-2-fluorophenyl) methyl] -1H-pyrazol-3-yl} -1H-isoindole-1,3 (2H) -dione Was obtained as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.9 (d, 1H), 7.88-7.95 (m, 4H), 7.54-7.60 (m, 1H), 7 20-7.27 (m, 2H), 6.41 (d, 1H), 5.49 (s, 2H). [ES + MS] m / z 356 (MH ^<+> ).

Intermediate 30: 2- {1-[(2-fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -1H-isoindole-1,3 (2H) -dione

1.00 g (4.69 mmol) of intermediate 27 was dissolved in 15 mL of DMF (dry) at 0 ° C. 0.188 g NaH (Aldrich, 4.69 mmol) was added to the solution and the mixture was stirred at 0 ° C. for 30 minutes. To this reaction mixture was added dropwise over 2 minutes to a solution of 1- (bromomethyl) -2-fluoro-3-methylbenzene (ALFAAESAR, 953 mg, 4.69 mmol) in 5 mL DMF (anhydrous). The mixture was stirred at room temperature for 3 hours. An additional equivalent of 1- (bromomethyl) -2-fluoro-3-methylbenzene (953 mg, 4.69 mmol) was added to the reaction and heated to 80 ° C. 0.2 eq. NaH was added approximately every 2 hours to 0.8 eq. After 44 hours of reaction, it was partitioned between NH ₄ Cl (saturated aqueous solution) and EtOAc. The organic fraction was dried over MgSO ₄ (anhydrous) and concentrated to dryness to give 1.64 g of crude, which was purified three times by Si (II) chromatography using a Hex / EtOAc gradient. 491 mg (yield: 31%) of 2- {1-[(2-fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -1H-isoindole-1,3 (2H) -dione Was obtained as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.88-7.96 (m, 5H), 7.23-7.28 (m, 1H), 7.07-7.11 (m, 2H), 6.39 (d, 1H), 5.40 (s, 2H), 2.24 (d, 3H). [ES + MS] m / z 336 (MH ^<+> ).

Intermediate 31: 2- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1H-isoindole-1,3 (2H) -dione

The title compound was prepared according to the procedure for Intermediate 30 described above using benzyl bromide (Aldrich, 401 mg, 2.345 mmol) and Intermediate 27 (500 mg, 2.345 mmol) as starting materials. 262 mg (yield: 37%) of 2- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1H-isoindole-1,3 (2H) -dione was obtained as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.89-7.98 (m, 5H), 7.29-7.40 (m, 5H), 6.39 (d, 1H), 5 .38 (s, 2H). [ES + MS] m / z 304 (MH ^<+> ).

Intermediate 32: 2- {1-[(2-chloro-6-fluorophenyl) methyl] -5-methyl-1H-pyrazol-3-yl} -1H-isoindole-1,3 (2H) -dione

2- (Bromomethyl) -1-chloro-3-fluorobenzene (Aldrich, 0.427 mL, 3.11 mmol), Intermediate 28 (589 mg, 2.59 mmol) and potassium carbonate (Aldrich, 430 mg) in a 100 mL round bottom flask. A solution of a mixture of 3.11 mmol) in ACN (40 mL) was stirred at reflux for 20 hours. The reaction was brought to room temperature, potassium carbonate was filtered and washed with DCM. The filtrate was evaporated to dryness to give 1.03 g of crude which was purified by silica gel chromatography using a Hex / EtOAc gradient (10% -80% -100%) to give the unwanted isomer (2- { 1-[(2-Chloro-6-fluorophenyl) methyl] -3-methyl-1H-pyrazol-5-yl} -1H-isoindole-1,3 (2H) -dione) was isolated. 314 mg (33% yield) of the title compound were obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.85-7.93 (m, 4H), 7.25-7.48 (m, 3H), 6.15 (s, 1H), 5 .36 (d, 2H), 2.43 (s, 3H). [ES + MS] m / z 370 (MH ^<+> ).

Intermediate 33: 1-[(3-chloro-2-fluorophenyl) methyl] -1H-pyrazol-3-amine

In a 50 mL round bottom flask, Intermediate 29 (532 mg, 1.495 mmol) was dissolved in ethanol (20 mL) and hydrazine monohydrate (FLUKA) (0.363 mL, 7.48 mmol) was added. The mixture was stirred at 80 ° C. for 16 hours. The white precipitate was filtered and washed with ethanol. The filtrate was evaporated to dryness to give 530 mg of crude which was purified by silica chromatography using a DCM / MeOH gradient (1% -10% -20%). 337 mg (yield: quantitative) of 1-[(3-chloro-2-fluorophenyl) methyl] -1H-pyrazol-3-amine was obtained as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.47-7.53 (m, 1H), 7.44 (d, 1H), 7.15-7.20 (m, 1H), 7 .05-7.10 (m, 1H), 5.41 (d, 1H), 5.11 (s, 2H), 4.60 (brs, 2H). [ES + MS] m / z 226 (MH ^<+> ).

Intermediate 34: 1-[(2-Fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-amine

The title compound was prepared according to the procedure for Intermediate 33 above, using Intermediate 30 (677 mg, 2.019 mmol) as the starting material. 340 mg (yield: 82%) of 1-[(2-fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-amine was obtained as an orange syrup. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.39 (d, 1H), 7.16-7.21 (m, 1H), 6.99-7.04 (m, 1H), 6 .89-6.94 (m, 1H), 5.39 (d, 1H), 5.04 (s, 2H), 4.56 (brs, 2H), 2.22 (d, 3H). [ES + MS] m / z 206 (MH ^<+> ).

Intermediate 35: 1- (phenylmethyl) -1H-pyrazol-3-amine

The title compound was prepared according to the procedure for Intermediate 33 described above, using Intermediate 31 (262 mg, 0.864 mmol) as the starting material. 140 mg (yield: 94%) of 1- (phenylmethyl) -1H-pyrazol-3-amine was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.42 (d, 1H), 7.16-7.33 (m, 5H), 5.40 (d, 1H), 5.02 (s 2H), 4.55 (brs, 2H). [ES + MS] m / z 174 (MH ^<+> ).

Intermediate 36: 1-[(2-chloro-6-fluorophenyl) methyl] -5-methyl-1H-pyrazol-3-amine

In a 100 mL round bottom flask, Intermediate 32 (314 mg, 0.849 mmol) was dissolved in EtOH (40 mL) and hydrazine monohydrate (Aldrich, 0.095 mL, 1.953 mmol) was added. The mixture was stirred at room temperature for 50 hours. The white precipitate was filtered and washed with EtOH. The filtrate was evaporated to dryness to give 330 mg of crude which was purified by silica chromatography using a DCM / MeOH gradient (0% -6% -20%). 148 mg (yield 73%) of 1-[(2-chloro-6-fluorophenyl) methyl] -5-methyl-1H-pyrazol-3-amine was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.18-7.42 (m, 3H), 5.18 (s, 1H), 5.01-5.02 (m, 2H), 4 .41 (brs, 2H), 2.23 (s, 3H). [ES + MS] m / z 240 (MH ^<+> ).

Intermediate 37: 1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-amine

Intermediate 6 (4 g, 15 mmol) was dissolved in a mixture of 25% aqueous solution of EtOH (30 mL) and NaOH (37.5 mL). The mixture was heated to reflux overnight. EtOH was then evaporated and the remaining aqueous fraction was partitioned between saturated aqueous NaCl (50 mL) and EtOAc (50 mL). The aqueous fraction was extracted with EtOAc (3 × 50 mL) and the resulting organic layer was dried over Na ₂ SO ₄ and concentrated to dryness to give 1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazole-3. -Amine (3.28 g, 14.6 mmol, 97%) was obtained as a yellow crystalline solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.17-7.30 (m, 3H), 7.04 (m, 1H), 5.56 (d, 1H), 5.27 (d, 2H ), 3.61 (brs, 2H); 210 (s, 3H). [ES + MS] m / z: 226.

  Intermediates 38-54 were prepared in a manner similar to that described for Intermediate 37, except that the corresponding Intermediate 6 (acetyl intermediate) was replaced with the intermediate shown in Table B.

(A) Purification by preparative HPLC using a SunFire chromatography column, method (40 — 00) ACN / H ₂ O (under neutral conditions).

Intermediate 51: 1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-amine

Intermediate 20 (370 mg, 1.473 mmol) was dissolved in EtOH (10 mL) and NaOH (aq 25%, 62.5 mmol) (10 mL) was added. The mixture was heated at 75 ° C. for 16 hours. The ethanol was then evaporated under vacuum and the aqueous fraction was partitioned between distilled water and EtOAc. The aqueous layer was extracted with EtOAc (x3) and DCM (x1), the organic layers were combined, dried over MgSO4 and concentrated to dryness to give a yellow solid. This was purified by silica gel chromatography using a DCM / MeOH gradient (0% -10%). The relevant fractions were combined and evaporated to give the title compound as an orange solid (174 mg; 57%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.35-7.46 (m, 2H), 7.05-7.14 (m, 2H), 5.36 (d, 1H), 5. 07 (s, 2H), 4.67 (brs, 2H). [ES + MS] m / z 210 (MH ^<+> ).

Intermediate 55: 1, 1-dimethylethyl {3-[(3-amino-1H-pyrazol-1-yl) methyl] -4-chlorophenyl} carbamate

A solution of Intermediate 22 (129 mg, 0.354 mmol) in EtOH (10 mL) and NaOH (aq, 12%) (10 mL) was heated to 50 ° C. for 4 h. At this time, the reaction was not completely complete but stopped. The amine group began to lose its protecting group Boc. EtOH was evaporated under vacuum and the aqueous fraction was partitioned between saturated brine and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO ₄ and concentrated to dryness to give the title compound (83 mg, 72.7%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.49 (br.s, 1H), 7.25-7.39 (m, 4H), 5.42 (d, 1H), 5.04 ( d, 1H), 4.58 (s, 2H), 1.44 (s, 9H). [ES + MS] m / z 323 [MH ^<+ >].

Intermediate 56: 1,1-dimethylethyl {3-[(3-amino-1H-pyrazol-1-yl) methyl] -2-methylphenyl} carbamate

A solution of intermediate 23 (185 mg, 0.537 mmol) in a mixture of EtOH (5 mL) and NaOH (aq, 12%) (5 mL) was heated at 75 ° C. for 2 h. Next, it heated at 50 degreeC for 3 hours. 5 ml NaOH (12%, aq) was added and the reaction was heated at 100 ° C. for 3 hours. The reaction mixture was stored in the refrigerator overnight. The next morning, the mixture was stirred at room temperature for 2 hours and then heated again at 75 ° C. for 1 hour. At that time, the reaction was not completed, but the reaction was stopped because the protecting group Boc almost disappeared. EtOH was evaporated under vacuum and the aqueous solution was extracted with EtOAc (x3). The organic layer was dried over anhydrous MgSO ₄ and concentrated to dryness to give a yellow solid. The solid was purified on 10 g of chromatography column Si (II) using a DCM / MeOH mixture as eluent. 1,1-dimethylethyl {3-[(3-amino-1H-pyrazol-1-yl) methyl] -2-methylphenyl} carbamate (64 mg, 0.201 mmol, 37%) was obtained as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 8.58 (br.s, 1H), 7.30 (d, 1H), 7.15-7.17 (m, 1H), 7.04- 7.09 (m, 1H), 6.71-6.74 (m, 1H), 5.40 (d, 1H), 5.03 (br.s, 2H), 4.54 (s, 2H) 2.10 (s, 3H), 1.44 (s, 9H). [ES + MS] m / z 303 (MH ^<+> ).

Intermediate 57: 1-[(2-chloro-6-fluorophenyl) methyl] -3-isothiocyanato-1H-pyrazole

To a solution of intermediate 37 (1 g, 4.4 mmol) in chloroform (60 mL) was added saturated aqueous NaHCO ₃ (60 mL) followed by thiophosgene (0.76 g, 6.6 mmol). The mixture was stirred vigorously overnight and the organic layer was separated using a hydrophobic frit. The organic fraction was concentrated to dryness to give 1-[(2-chloro-6-fluorophenyl) methyl] -3-isothiocyanato-1H-pyrazole (1.1 g, 4.1 mmol, 93%) as a yellow solid. . ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.24-7.36 (m, 3H), 7.07 (t, 1H), 6.16 (d, 1H), 5.39 (d, 2H) 210 (s, 3H). EM ⁺ (M / Z): 268.

  Intermediates 58-76 were prepared in a manner similar to that described for Intermediate 57 except that Intermediate 37 was replaced with that shown in Table C. The solvent used in the synthesis of the intermediate was DCM instead of chloroform.

(A) Wash the organic phase with water (b) Purify the crude on a silica gel cartridge using a Hex / ETOAc gradient (0-10%).

Intermediate 70: 1-[(2,6-difluorophenyl) methyl] -3-isothiocyanato-1H-pyrazole

In a 50 mL round bottom flask, Intermediate 51 (162 mg, 0.774 mmol) was dissolved in aqueous sodium bicarbonate (7 mL) and dichloromethane (7 mL), and thiophosgene (0.071 mL, 0.929 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and aqueous sodium bicarbonate. The phases were separated and the organic layer was dried over MgSO ₄ , filtered and concentrated to dryness in vacuo to give a brown solid (154 mg;). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.91 (d, 1H), 7.43-7.53 (m, 1H), 7.10-7.18 (m, 2H), 6. 42 (d, 1H), 5.35 (s, 2H). [ES + MS] m / z 252 (MH ^<+> ).

Intermediate 77: Ethyl 2- (3,5-dimethyl-1H-pyrazol-1-yl) propanoate

3,5-Dimethyl-1H-pyrazole (Aldrich, 8 g, 0.083 mol), anhydrous K ₂ CO ₃ (11.50 g, 0.083 mol) and ethyl 2-bromopropanoate (Aldrich, 15 g, 0.083 mol) Of the suspension in 50 mL anhydrous ACN was refluxed for 24 hours with mechanical stirring. The reaction was checked by TLC (iodine) and starting material was detected, so 0.2 equivalents of K ₂ CO ₃ was added to the mixture and refluxed over the weekend. Starting materials were still detected by checking the reactants. 0.2 equivalents of K ₂ CO ₃ was added to the mixture and refluxed for 24 hours. The reaction was stopped, but no progress of the reaction was observed. The reaction mixture was filtered. The solvent was evaporated under reduced pressure. The residue was diluted with 50 ml DCM and washed with water. The organic layer was separated and the aqueous fraction was extracted 3 times with 70 mL DCM. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated under reduced pressure. The residue was purified on a chromatographic column 70 g cartridge (ISOLUTE silica) using Hex / EtOAc 100/0 → 20/80 to give a colorless oil (11.6 g 71%). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 5.83 (s, 1H), 4.85 (q, 1H), 4.08-4.25 (m, 2H), 2.22-2.23 ( m, 6H), 1.79 (d, 3H), 1.23 (t, 3H).

Intermediate 78: 2- (3,5-dimethyl-1H-pyrazol-1-yl) propanohydrazide

To a stirred solution of hydrazine hydrate (FLUKA, 0.397 mol, 17.25 mL) in 100 mL of 95% EtOH, ethyl intermediate 77 (11.6 g, 0.066 mol) previously dissolved in 60 mL of EtOH was added dropwise. The reaction mixture was heated to 50 ° C. for 16 hours. The reaction was followed by TLC (iodine). The solvent was removed under vacuum to give a white solid (10.7 g, 98%), which was confirmed as the title compound. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.90 (br.s, 1H), 5.85 (s, 1H), 4.80 (q, 1H), 3.82 (br.s, 2H) 2.21-2.24 (m, 6H), 1.75 (d, 3H). [ES + MS] m / z 183 (MH ^<+> ).

Intermediate 79: Ethyl 3-amino-2-methyl-3-thioxopropanoate

A solution of a mixture of diphenylphosphinodithioic acid (Alfa-Aesar) (7.48 g, 29.9 mmol) and 2-cyanopropionic acid ethyl ester (ABCR, 1.980 mL, 14.94 mmol) in isopropanol (80 mL) for 8 hours. Heated to reflux and left at room temperature overnight. The reaction mixture was filtered and the filtrate was diluted with EtOAc, washed with 1N NaOH, brine, and then dried over Na ₂ SO ₄ . The crude was purified by silica gel chromatography using a Hex / EtOAc gradient. The relevant fractions were combined and concentrated to give the title compound as a yellow oily solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.60 (s, 1H), 9.40 (s, 1H), 4.05 (q, 2H), 3.74 (q, 1H), 1 .29 (d, 3H), 1.15 (t, 3H). [ES + MS] m / z 162 (MH +).

Intermediate 80: Ethyl 2- (4-methyl-1,3-thiazol-2-yl) propanoate

A solution of a mixture of intermediate 79 (500 mg, 3.10 mmol) and chloroacetone (Fluka, 0.300 ml, 3.39 mmol) in DMF (6 ml) was stirred at 80 ° C. for 5 hours. The reaction mixture was cooled to room temperature, treated with NaHCO ₃ and extracted with ethyl ether. The phases were separated and the organic phase was washed with brine and then dried over Na ₂ SO ₄ . Concentration gave the product as a yellow oil. ¹ HNMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.19 (s, 1H), 4.23 to 4.06 (m, 3H), 2.31 (s, 3H), 1.48 (d, 3H) ), 1.16 (t, 3H). [ES + MS] m / z 200 (MH +). This compound was then observed to undergo autooxidation at the asymmetric center to produce ethyl 2-hydroxy-2- (4-methyl-1,3-thiazol-2-yl) propanoate. After the presence of this compound was observed, this compound was actively synthesized as described in Intermediate 87 below.
Intermediate 81: 2- (4-Methyl-1,3-thiazol-2-yl) propanohydrazide and Intermediate 82: 2-hydroxy-2- (4-methyl-1,3-thiazol-2-yl) Propanohydrazide

Intermediate 80 (315 mg, 1.581 mmol) (some of which was later found to be in the form of an auto-oxidation product of Intermediate 80 (described below as Intermediate 87)) and hydrazine monohydrate ( A solution of 0.384 ml, 7.90 mmol) in ethanol (5 ml) was heated to reflux. After 3 hours, hydrazine monohydrate (Fluka, 0.384 ml, 7.90 mmol) was added and the reaction mixture continued to stir at reflux for 4 hours. The reaction mixture was concentrated and the residue was co-concentrated with toluene. The residue was pre-adsorbed on silica and purified by silica gel chromatography using a gradient of DCM and MeOH to give two products. Intermediate 81: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.36 (s, 1H), 7.12 (s, 1H), 4.27 (s, 2H), 3.92 (q, 1H), 2.30 (s, 3H), 1.40 (d, 3H). [ES + MS] m / z 186 (MH +). Intermediate 82: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.04 (s, 1H), 7.15 (s, 1H), 6.58 (s, 1H), 4.23 (s, 2H), 2.32 (s, 3H), 1.66 (s, 3H). [ES + MS] m / z 202 (MH +). Another method for making intermediate 82 is described below.

Intermediate 83: Ethyl 2- [4- (trifluoromethyl) -1,3-thiazol-2-yl] propanoate

A solution of a mixture of intermediate 79 (350 mg, 2.171 mmol) and 3-bromo-1,1,1-trifluoroacetone (Aldrich, 240 ml, 2.196 mmol) in DMF (6 ml) was stirred at 80 ° C. for 2 hours. . The reaction mixture was cooled to room temperature, treated with NaHCO ₃ and extracted with ethyl ether. The phases were separated and the organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude was purified by silica gel chromatography using a Hex / EtOAc gradient to give the title compound as a clear oil. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 8.47 (s, 1H), 4.39 (q, 1H), 4.13 (q, 2H), 1.54 (d, 3H), 1 .17 (t, 3H). [ES + MS] m / z 254 (MH +).

Intermediate 84: 2- [4- (trifluoromethyl) -1,3-thiazol-2-yl] propanohydrazide

A solution of intermediate 83 (240 mg, 0.948 mmol) and hydrazine monohydrate (0.230 ml, 4.74 mmol) in EtOH (5 ml) was heated to reflux. After 3 hours, hydrazine monohydrate (0.230 ml, 4.74 mmol) was added and the reaction mixture continued to stir at reflux for 4 hours. The reaction mixture was concentrated and the residue was co-concentrated with toluene to give the title compound as an oily solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.49 (s, 1H), 8.40 (s, 1H), 4.35 (s, 2H), 4.05 (q, 1H), 1 .46 (d, 3H). [ES + MS] m / z 240 (MH +).

Intermediate 85: 2-chloro-5-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1,3-thiazole

A solution of 3,5-dimethyl-1H-pyrazole (Aldrich, 114 mg, 1.190 mmol) in DMF (5 ml) was added over NaH (Aldrich, 34.3 mg, 1.42 mmol) at 0 ° C. under N ₂ atmosphere. did. The mixture was stirred for 5 minutes and a solution of 2-chloro-5- (chloromethyl) -1,3-thiazole (AK scientific, 200 mg, 1.19 mmol) in DMF (2 ml) was added. The mixture was stirred overnight. Finally, it was heated at 50 ° C. for 1 hour. DMF was removed by washing with 14 ml of EtOAc / NH ₄ Cl 1 N (1: 1) mixture. The organic layer was dried over Na ₂ SO ₄ and the solution was concentrated to dryness under vacuum to give the crude product, which was chromatographed (silica gel cartridge, Hex / EtOAc) to give the title compound. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.37 (s, 1H); 5.82 (s, 1H), 5.26 (s, 2H); 2.24 (s, 3H); 2.22 (S, 3H). [ES + MS] m / z: 228.1 (MH +).

Intermediate 86: Ethyl 2-bromo-2- (4-methyl-1,3-thiazol-2-yl) propanoate

To a solution of ethyl 2- (4-methyl-1,3-thiazol-2-yl) propanoate (3.91 g, 19.62 mmol) in toluene (95 mL) was added hydrochloric acid (1.77 mL, 21.58 mmol). . The mixture was stirred at room temperature for 10 minutes. The mixture was cooled to 0 ° C. and potassium bromide (MERCK, 2.57 g, 21.58 mmol) and hydrogen peroxide (2.37 mL, 25.5 mmol) were added. The reaction mixture was stirred at 0 ° C. for 5 h, at which point TLC (1: 1 EtOAc-Hex) indicated that the reaction was complete. The reaction mixture was quenched with 1N Na ₂ S ₂ O ₃ (60 mL) and saturated NaHCO ₃ (60 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 × 60 mL). The combined organics were washed with brine, dried over sodium sulfate and concentrated to give the title compound (5.02 g, 18.05 mmol, 92% yield) as a red oil. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.41 (s, 1H), 4.23 (q, 3H), 2.33 (s, 3H), 2.28 (s, 3H), 1.20 (t, 3H). [ES + MS] m / z 278 (MH ^<+> ).

Intermediate 87: Ethyl 2-hydroxy-2- (4-methyl-1,3-thiazol-2-yl) propanoate

A solution of intermediate 86 (5.02 g, 18.05 mmol) and silver oxide (2.09 g, 9.02 mmol) in acetonitrile (56 mL) and water (14 mL) was stirred at room temperature overnight. The reaction mixture was filtered through a celite pad to remove solids and the pad was washed with 95: 5 DCM-MeOH mixture (200 mL). The filtrate was concentrated to give 3.55 g of brown residue. The crude was purified on a 100 g silica gel cartridge using a hexane-ethyl acetate mixture (gradient 0-30%) to give 2.08 g (9.66 mmol, 54%) of the title compound as a yellow oil. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.19 (s, 1H), 6.71 (s, 1H), 4.08 (q, 2H), 2.31 (s, 3H), 1.68 (s, 3H), 1.13 (t, 3H). [ES + MS] m / z 216 (MH ^<+> ).

Intermediate 82 (another production method): 2-hydroxy-2- (4-methyl-1,3-thiazol-2-yl) propanohydrazide

A solution of intermediate 87 (2.08 g, 9.66 mmol) in ethanol (33 mL) was treated with hydrazine monohydrate (4.70 mL, 97 mmol) and the resulting mixture was heated to reflux for 3 hours. The reaction mixture was concentrated and dried under vacuum overnight to give the title compound as a white solid (1.94 g, 9.64 mmol, 100% yield). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.04 (s, 1H), 7.15 (s, 1H), 6.58 (s, 1H), 4.23 (s, 2H), 2.32 (s, 3H), 1.66 (s, 3H). [ES + MS] m / z 202 (MH ^<+> ).

Intermediate 88: ethyl 2- (methyloxy) -2- (4-methyl-1,3-thiazol-2-yl) propanoate

To a sodium hydride dispersed in 60% mineral oil (ALFAAESAR, 21 mg, 0.533 mmol), a solution of intermediate 87 (85 mg, 0.355 mmol) in DMF (4 mL) was added at 0 ° C. under nitrogen atmosphere. The resulting orange suspension was stirred for 10 minutes and iodomethane (ALDRICH, 0.033 mL, 0.533 mmol) was added. The reaction was stirred at room temperature for 1 hour. The mixture was then diluted with EtOAc (25 mL) and washed with 1N NH ₄ Cl (3 × 15 mL), brine, then dried over sodium sulfate and concentrated to give 78 mg of crude product. This was purified on a 2 g silica cartridge, eluting manually with a step gradient, 0-30% hexane-ethyl acetate, to give the title compound (51 mg, 0.220 mmol, 62.0% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.27 (s, 1H), 4.05-4.20 (m, 2H), 3.26 (s, 3H), 2.32 (s, 3H), 1.73 (s, 3H), 1.14 (t, 3H). [ES + MS] m / z 230 (MH ^<+> ).

Intermediate 89: Ethyldiazo (4-methyl-1,3-thiazol-2-yl) acetate

A solution of ethyl (4-methyl-1,3-thiazol-2-yl) acetate (ENAMINE, 300 mg, 1.619 mmol) in acetonitrile (ACN) (12 mL) with triethylamine (FLUKA, 0.339 mL, 2.429 mmol). Treated at 0 ° C. After 20 minutes, 4-acetamidobenzenesulfonyl azide (ALDRICH, 389 mg, 1.619 mmol) was added and the mixture was allowed to reach room temperature overnight. Next, 4-acetamidobenzenesulfonyl azide (ALDRICH, 94 mg, 0.391 mmol) was added and stirring was continued at room temperature for 2 hours. The reaction mixture was concentrated and the residue was kneaded with a 1: 1 Et ₂ O-hexane mixture and filtered. The solid was washed several times with the same mixture. The filtrate was concentrated to give 310 mg of crude product. This was purified on a 10 g silica cartridge and eluted manually using a linear gradient 0-50% hexane-ethyl acetate to give the title compound (200 mg, 0.947 mmol, 58.5% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.49 (d, 1H), 4.34 (q, 2H), 2.60 (s, 3H), 1.32 (t, 3H). [ES + MS] m / z 212 (MH ^<+> ).

Intermediate 90: ethyl (methyloxy) (4-methyl-1,3-thiazol-2-yl) acetate

A solution of intermediate 89 (400 mg, 1.894 mmol) in DCM (16 mL) was treated with rhodium (II) acetate dimer (ALDRICH, 17 mg, 0.038 mmol) and MeOH (0.230 mL, 5.68 mmol). The reaction mixture was stirred at room temperature for 4 hours and further heated at 40 ° C. for 4 hours. MeOH (0.230 mL, 5.68 mmol) was added and stirring was continued overnight at room temperature. A spatula tip amount of catalyst was added and heated at 40 ° C. for 4 hours. Evaporate 75% of the solvent and pour the residue directly into a 10 g silica cartridge eluting with a linear gradient 0-50% hexane-ethyl acetate to give the title compound as an oily liquid (350 mg, 1.626 mmol, 85.8). % Yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.32 (d, 1H), 5.22 (d, 1H), 4.16 (q, 2H), 3.38 (s, 3H), 2 .33 (s, 3H), 1.17 (t, 3H). [ES + MS] m / z 216 (MH ^<+> ).

Intermediate 91: Ethyl 3-amino-2,2-dimethyl-3-thioxopropanoate

A solution of a mixture of diphenyldithiophosphonic acid (ALFAAESAR, 1.42 g, 5.67 mmol) and 2-cyano-2-methylpropionic acid ethyl ester (ABCR, 0.412 mL, 2.83 mmol) in isopropanol (30 mL) for 4 hours. Heated to reflux. The reaction mixture was cooled to room temperature and a precipitate formed. The reaction flask was placed in the freezer for 1 hour. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (100 mL), washed with water (20 mL), 1N NaOH (20 mL), saturated NaHCO ₃ (20 mL), then dried over sodium sulfate and concentrated. The resulting oil was poured into a 25 g silica cartridge and eluted using a linear gradient 0-50% hexane-ethyl acetate to give the title compound (110 mg, 0.628 mmol, 22.2% yield). The batch containing another impurity was loaded onto a 10 g silica cartridge and eluted using a linear gradient 0-50% hexane-ethyl acetate to recover the title compound (120 mg, 0.685 mmol, 24.17% yield). Overall yield: (230 mg, 1.313 mmol, 46.32%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.70 (brs, 1H), 8.86 (brs, 1H), 4.05 (q, 2H), 1.39 (s, 6H), 1 .15 (t, 3H). [ES + MS] m / z 176 (MH ^<+> ).

Intermediate 92: Ethyl 2-methyl-2- (4-methyl-1,3-thiazol-2-yl) propanoate

A solution of a mixture of intermediate 91 (220 mg, 1.255 mmol) and chloroacetone (FLUKA, 0.111 mL, 1.255 mmol) in DMF (4 mL) is stirred at 80 ° C. for 5 hours and stirred at 50 ° C. overnight. Continued. Chloroacetone (FLUKA, 0.060 mL, 0.678 mmol) was added and stirring was continued at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with diethyl ether (50 mL), then washed with 1N NH ₄ Cl (2 × 20 mL), saturated NaHCO ₃ (20 mL), brine (20 mL), dried over Na ₂ SO ₄ and concentrated. The title compound (240 mg, 1.125 mmol, 90% yield) was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.17-7.20 (m, 1H), 4.07 (q, 2H), 2.31 (d, 3H), 1.58 (s, 6H), 1.12 (t, 3H). [ES + MS] m / z 214 (MH ^<+> ).

  Intermediates 93-95 were prepared in a similar manner as described for intermediate 84 except that intermediate 83 (ester) was replaced with that shown in Table D. A change in the purification step was also shown.

a) The residue was pre-adsorbed on silica, loaded onto a 10 g silica gel cartridge and eluted with a linear gradient: 0-20% MeOH-DCM.

Intermediate 96: (2,6-difluoro-3-nitrophenyl) methanol

2,6-difluoro-3-nitrobenzoic acid (APOLLO, 500 mg, 2.462 mmol) as a starting material, as described in compound 18 in the reference Bioorganic and Medicinal Chemistry, 1999, 7 (11), page 2660. The title compound was prepared according to the manufacturing method. The crude was purified on a 20 g silica gel cartridge using a linear gradient 0-5% DCM / MeOH to give the title compound (340 mg, 1.798 mmol, 73% yield) as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 8.15-8.30 (m, 1H), 7.30-7.45 (m, 1H), 5.50 (t, 1H), 4. 55 (d, 2H).

Intermediate 97: (3-amino-2,6-difluorophenyl) methanol

Intermediate 96 (60 mg, 0.317 mmol) was dissolved in 10 mL of ethyl acetate. The solution was passed through an H-cube system using a Pd (C) cartridge, and after solvent removal, the title compound (47 mg, 0.295 mmol, 93% yield) was obtained as a white solid. Starting from 282 mg (1.49 mmol) of intermediate 96, the same conditions yielded an additional batch of the title compound, then these two batches were combined to yield 230 mg (1.45 mmol, 97% yield) of the title compound as a white solid Obtained as a solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 6.60-6.80 (m, 2H), 5.08 (t, 1H), 4.91 (brs, 2H), 4.42 (d, 2H).

Intermediate 98: [3- (acetylamino) -2,6-difluorophenyl] methyl acetate

References: Bioorganic and Medicinal Chemistry, 1999, 7 (11), pg. The title compound was prepared from Intermediate 97 (278 mg, 1.747 mmol) according to the procedure described for compound 20 (page 2660) in 2647-2666. This process excluded the use of pyrrolidine. The reaction composition was purified on a 10 g silica cartridge and eluted using a linear gradient 0-50% hexane-ethyl acetate to give the title compound (345 mg, 1.419 mmol, 81% yield) as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.77 (brs, 1H), 7.77-7.88 (m, 1H), 7.05-7.15 (m, 1H), 5. 12 (s, 2H), 2.06 (s, 3H), 2.02 (s, 3H). [ES + MS] m / z 244 (MH +).

Intermediate 99: N- [2,4-difluoro-3- (hydroxymethyl) phenyl] acetamide

References: Bioorganic and Medicinal Chemistry, 1999, 7 (11), pg. The title compound was prepared from intermediate 98 (340 mg, 1.398 mmol) according to the procedure described for compound 21 (page 2660) in 2647-2666 to give the desired compound (236 mg, 1.114 mmol, 80% yield). Obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.69 (brs, 1H), 7.67-7.77 (m, 1H), 6.95-7.06 (m, 1H), 5. 26 (t, 1H), 4.49 (d, 2H), 2.06 (s, 3H). [ES + MS] m / z 202 (MH +).

Intermediate 100: [3- (acetylamino) -2,6-difluorophenyl] methylmethanesulfonate

References: Bioorganic and Medicinal Chemistry, 1999, 7 (11), pg. Prepare the compound from intermediate 99 (236 mg, 1.173 mmol) according to the procedure described for compound 22 (page 2660) in 2647-2666 to give the title compound (216 mg, 0.696 mmol, 59.3% yield). Obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.82 (brs, 1H), 7.84-7.95 (m, 1H), 7.12-7.20 (m, 1H), 5. 32 (s, 2H), 3.25 (s, 3H), 2.07 (s, 3H). [ES + MS] m / z 280 (MH +).

Intermediate 101: (3-amino-2-fluorophenyl) methanol

3-Amino-2-fluorobenzoic acid (APIN, 250 mg, 1.612 mmol) was dissolved in 10 mL anhydrous THF under N ₂ atmosphere. The solution was cooled at 0 ° C. in an ice-water bath. LiAlH ₄ (FLUKA, 183 mg, 4.83 mmol) was added. The reaction was stirred at room temperature under a nitrogen atmosphere. After 2 hours, 1 equivalent of LiAlH ₄ (FLUKA, 61 mg, 1.62 mmol) was added to the mixture and the reaction was stirred at room temperature overnight. Another equivalent of LiAlH ₄ (FLUKA, 61 mg, 1.62 mmol) was added. After 5 hours, the reaction mixture was quenched by the addition of MeOH. The solvent was evaporated to give an orange syrup that was dissolved in EtOAc and partitioned using saturated NaHCO ₃ (aq) (10 mL saturated solution +15 mL distilled water). The aqueous phase was extracted with EtOAc, the organic layers were combined, dried over MgSO ₄ (anh), filtered off and concentrated. The crude was purified on a silica gel cartridge using a linear gradient 0-85% DCM / MeOH to give the title compound (114 mg, 0.808 mmol, 50.1% yield) as a yellow syrup. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 6.50-6.85 (m, 3H), 4.95-5.08 (m, 3H), 4.44 (d, 2H).

Intermediate 102: Ethyl [2-fluoro-3- (hydroxymethyl) phenyl] carbamate

A stirred suspension of sodium carbonate (78 mg, 1.573 mmol) and intermediate 101 (222 mg, 1.573 mmol) in 10 mL of water was cooled at 0 ° C. under a nitrogen atmosphere. Ethyl chlorocarbonate (ALDRICH, 171 mg, 1.573 mmol) was added dropwise. The reaction was stirred at 0 ° C. for 1 hour 30 minutes and allowed to warm to room temperature. The reaction crude was partitioned with Et ₂ O. The organic layer was dried over MgSO4 (anh), filtered and concentrated to give the title compound (359 mg, 1.600 mmol, quantitative yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.21 (brs, 1H), 7.45-7.55 (m, 1H), 7.05-7.22 (m, 2H), 5. 24 (brs, 1H), 4.51 (s, 2H), 4.10 (q, 2H), 1.22 (t, 3H). [ES + MS] m / z 214 (MH +).

Intermediate 103: Ethyl [3- (bromomethyl) -2-fluorophenyl] carbamate

Intermediate 102 (250 mg, 1.173 mmol) was dissolved in 15 mL DCM at 0 ° C. under a nitrogen atmosphere. Carbon tetrabromide (ALDRICH, 583 mg, 1.759 mmol) and triphenylphosphine (ALDRICH, 461 mg, 1.1759 mmol) were added to this solution. After stirring the reaction overnight at room temperature, the solvent was evaporated. The reaction crude was purified on a 20 g silica cartridge eluting with a linear gradient 0-20% hexane-ethyl acetate to give the title compound (255 mg, 0.877 mmol, 74.8% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.37 (brs, 1H), 7.56-7.66 (m, 1H), 7.18-7.29 (m, 1H), 7. 08-7.17 (m, 1H), 4.68 (s, 2H), 4.12 (q, 2H), 1.23 (t, 3H). [ES + MS] m / z 276 (MH +).

Intermediate 104: ethyl (3-{[3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1H-pyrazol-1-yl] methyl} -2-fluorophenyl ) Carbamate

Intermediate 27 (236 mg, 1.108 mmol) was dissolved in 15 mL of acetonitrile under a nitrogen atmosphere. Potassium carbonate (ALDRICH, 153 mg, 1.108 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 20 minutes. Intermediate 103 (255 mg, 0.924 mmol) was added and the reaction was heated at 70 ° C. for 2 hours and then stirred at room temperature overnight. The solvent was evaporated and the reaction crude was partitioned between DCM and distilled water. The organic layer was dried over MgSO ₄ (anh), filtered and concentrated. The solid was purified on a silica cartridge. Since two positional isomers were observed, a new purified and unnecessary isomer of ethyl (3-{[5- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1H-pyrazol-1-yl] methyl} -2-fluorophenyl) carbamate was isolated. Purification by preparative HPLC was performed using a SUNFIRE (30 × 150 mm) column and a gradient 40% -80% ACN: NH ₄ CO ₃ (aq, 10 mM) to give the title compound (90 mg, 0.220 mmol, 23.9% yield). Obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.36 (brs, 1H), 7.86-7.99 (m, 5H), 7.57-7.66 (m, 1H), 7. 08-7.16 (m, 1H), 6.94-7.02 (m, 1H), 6.39 (d, 1H), 5.42 (s, 2H), 4.11 (q, 2H) 1.22 (t, 3H).

Intermediate 105: N- (3-{[3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1H-pyrazol-1-yl] methyl} -2,4 -Difluorophenyl) acetamide

Intermediate 27 (210 mg, 0.901 mmol) was dissolved in 10 mL acetonitrile under a nitrogen atmosphere. Potassium carbonate (ALDRICH, 124 mg, 0.752 mmol) was added in one portion and the reaction mixture was stirred for 20 minutes. Intermediate 99 (210 mg, 0.752 mmol) was then added and the reaction mixture was heated at 70 ° C. for 1 hour and then at 50 ° C. overnight. The solvent was removed and the reaction crude was partitioned between DCM and distilled water. The organic layer was dried, concentrated and purified on a silica 10 g Merck cartridge using DCM: MeOH as solvent. A second purification was performed on a silica 10GM Merck cartridge (using a less polar elution mixture) using DCM: MeOH as a solvent to give the title compound (70 mg, 0.177 mmol, 23.5% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.78 (brs, 1H), 7.79-7.98 (m, 6H), 7.06-7.15 (m, 1H), 6. 34-6.38 (m, 1H), 5.43 (s, 2H), 2.05 (s, 3H). [ES + MS] m / z 397 (MH +).

  Intermediates 106-108 were prepared by a method similar to Intermediate 6 except that benzyl bromide (2- (bromomethyl) -1-chloro-3-fluorobenzene) was replaced with that shown in Table E. Benzyl bromide was dissolved in anhydrous DMF and added dropwise. A change in the purification step was also shown.

a) The reaction was partitioned between saturated NH 4 Cl and DCM and purified on a FlashMaster on a 10 g silica gel cartridge using a hexane / AcOEt gradient (0-70%).

b) The reaction was partitioned between saturated NH 4 Cl and DCM and purified on a FlashMaster on a 25 g silica gel cartridge using a hexane / AcOEt gradient (0-50%).
Intermediates 109-112 were prepared in a manner similar to that described for Intermediate 37 except that Intermediate 6 (acetyl intermediate) was replaced with the intermediates shown in Table F. A change in the purification step was also shown.

a) The remaining aqueous fraction was diluted with distilled water and EtOAc. The aqueous layer was extracted with EtOAc (x3), then the organic layers were combined, dried over anhydrous MgSO4 and concentrated.

b) Purified by preparative HPLC using an XTERRA chromatography column (30 × 150 mm), method (0_80) ACN (0.1% TFA) / H ₂ O (0.1% TFA).

Intermediate 113: ethyl {3-[(3-amino-1H-pyrazol-1-yl) methyl] -2-fluorophenyl} carbamate

Intermediate 103 (86 mg, 0.211 mmol) was dissolved in EtOH (10 mL) and hydrazine monohydrate (FLUKA, 31 μL, 0.632 mmol) was added. The reaction was stirred overnight. The reaction crude was filtered to remove a white precipitate. The filtrate was concentrated and dissolved in DCM to precipitate a white solid and the solution was filtered again. The filtrate was concentrated to give the title compound (56 mg, 0.191 mmol, 91% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.28 (brs, 1H), 7.48-7.58 (m, 1H), 7.41 (d, 1H), 7.01-7. 10 (m, 1H), 6.78-6.85 (m, 1H), 5.40 (d, 1H), 5.05 (s, 2H), 4.57 (brs, 2H), 4.11 (Q, 2H), 1.22 (t, 3H). [ES + MS] m / z 279 (MH ^<+> ).

Intermediate 114: N- {3-[(3-amino-1H-pyrazol-1-yl) methyl] -2,4-difluorophenyl} acetamide

Intermediate 104 (95 mg, 0.240 mmol) was dissolved in EtOH (5 mL) and hydrazine monohydrate (FLUKA, 15 μL, 0.312 mmol) was added. The reaction was stirred overnight. The reaction crude was filtered to remove a white precipitate. The filtrate was concentrated to give the title compound (77 mg, 0.289 mmol, quantitative yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 9.72 (brs, 1H), 8.01-8.08 (m, 1H), 7.78-7.87 (m, 1H), 7. 36 (s, 1H), 5.35 (s, 1H), 5.07 (s, 2H), 4.55 (brs, 2H), 2.04 (s, 3H).

  Intermediates 115-120 were prepared in a manner similar to Intermediate 57 except that Intermediate 37 was replaced with that shown in Table G. The solvent used for the synthesis of these intermediates was DCM, not chloroform. Reaction time: 30 minutes to 8 hours. A change in the purification step was also shown.

a) The reaction was diluted with DCM and aqueous sodium bicarbonate. The phases were separated and the organic phase was dried over MgSO4 (anh), filtered and concentrated.

b) The reaction was diluted with DCM and distilled water. The phases were separated and the organic phase was dried over MgSO4 (anh), filtered and concentrated.

Intermediate 121: Ethyl (2-fluoro-3-{[3-({5- [1-hydroxy-1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4) -Thiadiazol-2-yl} amino) -1H-pyrazol-1-yl] methyl} phenyl) carbamate

A solution of intermediate 118 (ethyl {2-fluoro-3-[(3-isothiocyanato-1H-pyrazol-1-yl) methyl] phenyl} carbamate (105 mg, 0.328 mmol)) in 10 ml DCM and intermediate 82 ( 2-Hydroxy-2- (4-methyl-1,3-thiazol-2-yl) propanohydrazide (73 mg, 0.361 mmol)) was stirred at room temperature for 1 hour. The solvent was evaporated to give an orange solid to give ethyl [2-fluoro-3-({3-[({2- [2-hydroxy-2- (4-methyl-3H-114,3-thiazole-2 -Yl) propanoyl] hydrazino} carbonothioyl) amino] -1H-pyrazol-1-yl} methyl) phenyl] carbamate (138 mg, 0.264 mmol). This solid was dissolved in ₂ mL of H ₂ SO ₄ (conc) and the reaction mixture was stirred at room temperature for 1 hour 30 minutes. The reaction was then neutralized by adding NH3 (aq, 32%) and partitioned with AcOEt (15 mLX3). The organic layer was dried over MgSO ₄ , filtered and concentrated to give 103 mg of an orange solid which was purified XTERRA chromatography column (19 mm × 150 mm), method (25 — 100) ACN / H ₂ O (0.1% Purification by HPLC using NH ₄ CO _{3 (} 10 mM). After the corresponding fractions were combined, 23 mg of a light orange solid was obtained and judged to be the title compound from its characteristics. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.86 (brs, 1H), 9.30 (brs, 1H), 7.71 (d, 1H), 7.53-7.61 (m, 1H), 7.28 (s, 1H), 7.19 (s, 1H), 7.03-7.11 (m, 1H), 6.84-6.91 (m, 1H), 5.98 (D, 1H), 5.26 (s, 2H), 4.11 (q, 2H), 2.29 (s, 3H), 1.97 (s, 3H), 1.22 (t, 3H) . [ES + MS] m / z 504 (MH ^<+> ).

Examples Method A
Example 1: 5- [1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -N- (1-{[2- (trifluoromethyl) phenyl] methyl} -1H-pyrazole- 3-yl) -1,3,4-thiadiazol-2-amine

Intermediate 61 (3-isothiocyanato-1-{[2- (trifluoromethyl) phenyl] methyl} -1H-pyrazole, 300 mg, 1.059 mmol) and intermediate 78 (2- (3,5-dimethyl-1H- A solution of pyrazol-1-yl) propanohydrazide, 193 mg, 0.231 mmol) in 5 ml DCM (anh) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and 2- [2- (3,5-dimethyl-1H-pyrazol-1-yl) propanoyl] -N- (1-{[2- (trifluoromethyl) phenyl] methyl} -1H -Pyrazol-3-yl) hydrazinecarbothioamide (460 mg, 93%) was obtained as a yellow solid ([ES + MS] m / z 466 (MH ^<+> )). The solid was dissolved in 4 mL of H ₂ SO ₄ (conc) and stirred at room temperature for 3 hours. The resulting mixture was neutralized with 32% NH ₃ (aq) in an ice bath until a basic pale yellow precipitate was formed, and the resulting precipitate was filtered off. This was washed with cold water and dried under vacuum to give a pale yellow solid which was dissolved in EtOAc and washed with water. The organic layer was dried over MgSO ₄ (anh), filtered and dried under vacuum to give the title compound (56 mg, 81%) as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.91 (s, 1H), 7.75-7.80 (m, 2H), 7.59-7.64 (m, 1H), 7. 50-7.55 (m, 1H), 7.06-7.09 (m, 1H), 6.01 (d, 1H), 5.83 (s, 1H), 5.76 (q, 1H) 5.40 (s, 2H), 2.23 (s, 3H), 2.07 (s, 3H), 1.78 (d, 3H). [ES + MS] m / z 448 (MH ^<+> ).
Examples 2-17 were prepared by a method analogous to that described in Example 1, replacing isothiocyanate and hydrazide intermediates 61 and 78 with those shown in Table 1. A change in the purification step was also shown.

(A) The initial precipitate does not require EtOAc / water treatment.

(B) The precipitate was purified by preparative HPLC under neutral conditions using a SunFire chromatography column (30 mm × 150 mm), method (40 — 100) ACN / H 2 O.

(C) The initial precipitate was partitioned between DCM / water.

(D) The product was dissolved in DCM (HPLC grade) and precipitated with hexane (HPLC grade).

Example 19: N- {1-[(2-chloro-6-fluorophenyl) methyl] -5-methyl-1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H- Pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine

165 mg of intermediate 76 (1-[(2-chloro-6-fluorophenyl) methyl] -3-isothiocyanato-5-methyl-1H-pyrazole, 0.586 mmol) was dissolved in 15 mL of anhydrous DCM and 107 mg (0 .586 mmol) of intermediate 78 (2- (3,5-dimethyl-1H-pyrazol-1-yl) propanohydrazide) was added. The mixture was stirred at room temperature for 20 hours and the solvent was evaporated to yield 267 mg (98% yield) of N- {1-[(2-chloro-6-fluorophenyl) methyl] -5-methyl-1H-pyrazole-3. -Il} -2- [2- (3,5-dimethyl-1H-pyrazol-1-yl) propanoyl] hydrazinecarbothioamide was obtained as an orange solid ([ES + MS] m / z 464 (MH ⁺ )). A solution formed by dissolving this solid in 3 mL of H ₂ SO ₄ (conc) was stirred at room temperature for 2 hours. The reaction was carefully neutralized with aqueous ammonia (32%) until a basic precipitate had formed. The precipitate was filtered to give 231 mg of crude which was purified by silica gel chromatography using a DCM / MeOH gradient (1% -10% -20%). 73 mg (yield: 28%) of the title compound were obtained as a white solid. The second fraction (163 mg) was purified by silica gel chromatography using a DCM / MeOH gradient (1% -10% -20%) and then purified twice by preparative HPLC under the following conditions: SUNFIRE C18 3.5 μm, gradient: water-ACN 60: 40 → 0: 100 (20 minutes), 254 nm. The relevant fractions were collected to give 30 mg (yield: 12%) of the title compound as a white solid (overall yield: 40%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.45 (brs, 1H), 7.15-7.44 (m, 3H), 5.85 (s, 1H), 5.76 (s, 1H), 5.69 (q, 1H), 5.20 (d, 2H), 2.35 (s, 3H), 2.24 (s, 3H), 2.13 (s, 3H), 1. 79 (d, 3H). [ES + MS] m / z 446 (MH ^<+> ).

Method B
Example 20: 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- {1-[(2-methylphenyl) methyl] -1H-pyrazol-3-yl} -1,3,4-thiadiazol-2-amine

Intermediate 59 (3-isothiocyanato-1-[(2-methylphenyl) methyl] -1H-pyrazole, 127 mg, 0.554 mmol) and intermediate 78 2- (3,5-dimethyl-1H-pyrazole-1- Il) A solution of propanohydrazide (101 mg, 0.554 mmol) in 5 ml DCM (anh) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give 2- [2- (3,5-dimethyl-1H-pyrazol-1-yl) propanoyl] -N- {1-[(2-methylphenyl) methyl] -1H-pyrazole- 3-yl} hydrazinecarbothioamide (223 mg, 0.542 mmol, 98%) was obtained as a yellow solid ([ES + MS] m / z 412 (MH ⁺ )). This solid was dissolved in POCl ₃ (3 mL) and stirred at reflux for 2 hours 30 minutes. The solvent is removed in vacuo, the residue is partitioned between DCM and distilled H ₂ O, the organic layer is dried over MgSO ₄ (anh), filtered and concentrated to give a solid that is filtered with SunFire chromatography. Purification by preparative HPLC using a chromatography column (30 mm × 150 mm), method (50 — 100) ACN / H 2 O under neutral conditions afforded the title compound as a white solid (96 mg, 46%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.87 (br.s.1H), 7.68 (d, 1H), 7.10-7.18 (m, 3H), 7.01- 7.04 (m, 1H), 5.93 (d, 1H), 5.85 (br.s, 1H), 5.77 (q, 1H), 5.20 (br.s, 2H), 2 .35 (s, 3H), 2.25 (s, 3H), 2.11 (s, 3H), 1.79 (d, 3H), [ES + MS] m / z 394 (MH ⁺ ).

Examples 21-27 were prepared in a similar manner as described in Example 20, replacing the isothiocyanate and hydrazide intermediates with those shown in Table 2. If the purification method used was different from Example 20, this was indicated.

(A) Method (40_100) ACN / H2O, under neutral conditions.

(B) Method (30 — 100) ACN (0.1% TFA) / H ₂ O (0.1% TFA). The corresponding salt was obtained, which was basified with NH ₃ (aq, 32%) and partitioned between AcOEt / H ₂ O. The organic layer was dried over MgSO ₄ (anh), filtered and the solvent was removed.

(C) Method (20 — 100) ACN / H ₂ O, under neutral conditions.

Method C
Example 28: N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazole-1- Yl) ethyl] -1,3,4-thiadiazol-2-amine

Intermediate 78 (2- (3,5-dimethyl-1H-pyrazol-1-yl) propanohydrazide, 0.75 g, 4.1 mmol) and intermediate 57 (1-[(2-chloro-6-fluorophenyl) ) Methyl] -3-isothiocyanato-1H-pyrazole, 1.1 g, 4.1 mmol) was suspended in EtOH (30 mL) and the mixture was heated to reflux for 2 hours. The resulting white solid was then filtered off and washed with EtOH to give a hydrazine carbothioamide intermediate (1.7 g, 3.8 mmol, 92%, [ES + MS] m / z 450 (MH ⁺ )). This intermediate N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -2- [2- (3,5-dimethyl-1H-pyrazol-1-yl) ) Propanoyl] hydrazinecarbothioamide (1.65 g, 3.7 mmol) was dissolved in concentrated H ₂ SO ₄ (15 mL) and the mixture was stirred for 2 h. 33% aq. NH ₃ was added dropwise at ice bath temperature to neutralize to give a white precipitate, which was filtered off and dried under vacuum to give the title compound as a white solid (1.26 g, 2.9 mmol, 78. 4%). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.21-7.34 (m, 3H), 7.05 (m, 1H), 5.98 (d, 1H), 5.82 (d, 1H) 5.69 (q, 1H), 5.36 (d, 2H), 2.30 (s, 3H), 2.26 (s, 3H), 1.99 (d, 2H). [ES + MS] m / z: 432 (MH ^<+> ).

Examples 29-33 were prepared in a similar manner as described in Example 28 except that the isothiocyanate and hydrazide intermediates were replaced with those shown in Table 3. If the solids were not filtered during neutralization, the purification process was indicated in a footnote.

(A) The resulting suspension was diluted with EtOAc and water. The organic phase was separated, washed with brine, then dried over sodium sulfate, concentrated and the crude was purified by silica gel chromatography using a DCM / MeOH gradient to give the title compound.

(B) The aqueous mixture was extracted with ethyl acetate. The organic extract was washed with brine, then dried over sodium sulfate and concentrated. The residue was kneaded with ethyl ether and the resulting solid was filtered and washed with ethyl ether.

Example 34: N- {1-[(4-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl]- 1,3,4-thiadiazol-2-amine

Intermediate 50 (1-[(4-chlorophenyl) methyl] -1H-pyrazol-3-amine, 63 mg, 0.3 mmol) was added to chloroform (1.2 mL) and aq. Dissolved in a mixture of NaHCO ₃ (saturated) (1.2 mL). Thiophosgene (41 mg, 0.36 mmol) was added and the mixture was stirred vigorously for 10 minutes. The organic phase was then separated using a hydrophobic frit and concentrated to dryness to give a pale yellow oil (72 mg, [ES + MS] m / z: 250 (MH +)). The crude oil and intermediate 78 (53 mg, 0.29 mmol) were dissolved in DCM (6 mL) and the mixture was stirred for 1 hour 30 minutes. The resulting solution was concentrated to dryness to give a pale yellow oil (125 mg, [ES + MS] m / z: 432 (MH ⁺ )), which was dissolved in concentrated H ₂ SO ₄ (10 mL) for 1 hour 30 at room temperature. Stir for minutes. The resulting solution was carefully neutralized with a 28% aqueous solution of NH ₃ at ice-cold temperature to produce a white precipitate. The resulting solid was filtered off, washed with water (2 ×) and dried under vacuum to give the title compound as a white solid (35 mg, 30%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.87 (s, 1H), 7.74 (d, 1H), 7.37 (d, 2H), 7.24 (d, 2H), 5 .95 (d, 1H), 5.84 (s, 1H), 5.76 (q, 1H), 5.20 (s, 2H), 2.24 (s, 3H), 2.09 (s, 2H), 1.78 (d, 3H). [ES + MS] m / z: 414 (M ^<+> ).

Example 35: 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- (1-{[4- (trifluoromethyl) phenyl] methyl} -1H-pyrazole- 3-yl) -1,3,4-thiadiazol-2-amine

This compound was prepared in a similar manner as Example 34 starting from intermediate 54. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.78 (d, 1H), 7.67 (d, 2H), 7.42 (d, 2H), 5.98 (d, 1H), 5.82 (s, 1H), 5.76 (q, 1H), 5.33 (s, 2H), 2.23 (s, 3H), 2.06 (s, 2H), 1.78 (d 3H); [ES + MS] m / z. 448 (MH ^<+> ).

Example 36: N- {1-[(2-chloro-5-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazole-1- Yl) ethyl] -1,3,4-thiadiazol-2-amine

Intermediate 21 (N- {1-[(2-chloro-5-fluorophenyl) methyl] -1H-pyrazol-3-yl} acetamide, 320 mg, 1.2 mmol) was dissolved in EtOH (10 mL) and aq. 25% NaOH (14 mL) was added and the mixture was heated to reflux overnight. Volatile EtOH was removed by evaporation, and the aqueous solution was further dissolved in a saturated aqueous NaCl solution. The aqueous layer was then extracted with EtOAc (3 × 15 mL), dried over Na ₂ SO ₄ and concentrated to dryness to give a colorless oil (197 mg, [ES + MS] m / z: 226 (MH ⁺ )). This oil was dissolved in a mixture of chloroform (5 mL) and saturated aqueous NaHCO ₃ (5 mL). To the resulting solution, thiophosgene (120 mg, 1.04 mmol) was added and the mixture was allowed to react for 20 minutes. The organic layer was then separated using a hydrophobic frit and concentrated in vacuo to give a yellow oil (248 mg, [ES + MS] m / z: 268 (MH ⁺ )). This crude and intermediate 78 (110 mg, 0.93 mmol) were dissolved in DCM (10 mL) and the mixture was allowed to react overnight. The resulting solution was concentrated to dryness and suspended in concentrated H ₂ SO ₄ (15 mL) and stirred at room temperature for 2 hours. The resulting solution was carefully neutralized with a 28% aqueous solution of NH ₃ at ice-cold temperature to produce a white precipitate. The formed solid was filtered off, washed with water (2 ×), dried under vacuum, and purified by HPLC (Agilent 1200, Sunfire-19, 40 → 100% ACN / water, 21 minutes) to purify the title compound as a white solid (95 mg 18%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.91 (brs, 1H), 7.78 (d, 1H), 7.52 (dd, 1H), 7.22 (m, 1H), 6 .89 (m, 1H), 5.99 (d, 1H), 5.82 (s, 1H), 5.75 (q, 1H), 5.30 (s, 2H), 2.23 (s, 3H), 2.07 (s, 3H), 1.77 (d, 2H). [ES + MS] m / z: 433 (MH ^<+> ).

Example 37: N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3,5-dimethyl-1H-pyrazol-1-yl) Methyl] -1,3-thiazol-2-amine

To a solution of intermediate 85 (2-chloro-5-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1,3-thiazole, 40 mg, 0.18 mmol) in toluene (1 ml), 1-[(2-Chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-amine (ARTCHEM, 44 mg, 0.19 mmol), sodium t-butoxide (25 mg, 0.26 mmol), BINAP (7 mg, 0 0.011 mmol) and Pd ₂ (dba) ₃ (5 mg, 0.006 mmol) were added sequentially. The resulting suspension was deoxygenated for 5 minutes and microwave heated in a sealed container at 120 ° C. for 30 minutes. After filtering the reaction mixture, toluene was evaporated and the residue was purified by chromatography (silica gel cartridge, Hex / EtOAc) to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.65 (s, 1H); 7.44-7.24 (m, 3H); 7.11 (s, 1H), 5.94 (s, 1H); 5.78 (s, 1H); 5.32 (s, 2H); 5.17 (s, 2H); 2.27 (s, 3H); 2.07 (s, 3H). [ES + MS] m / z: 417 (MH ^<+> ).

The compounds in Table 4 (Examples 38-65) were purchased from ARTCHEM and tested with InhA enzyme and TB growth inhibition assay. These compounds can be prepared using procedures analogous to those described above.

Chiral separation of the racemate of Example 38

38 mg of Example 38 (racemic mixture) was separated using CHIRALPAK-AD 20 × 250 mm column, F = 17 mL / min, 254 nm using a mixture of hexane-ethanol 40:60. 38 mg was dissolved in 3 mL of ethanol / isopropanol / methanol mixture under heating (the product is very insoluble). Four injections were required to purify all samples. Since heating of the dissolved sample began during the injection, additional heating was required before each injection. Separation was complete and the relevant fractions were collected to give both enantiomers which were further purified on a 1 g silica gel cartridge using a 25: 1 mixture of DCM / MeOH (both solvents HPLC grade).

Example 66: N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1R) -1- (3-methyl-1H-pyrazole- 1-yl) ethyl] -1,3,4-thiadiazol-2-amine

Isomer 1, first HPLC eluent: 10.5 mg, white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.41 (d, 1H), 7.36 (d, 1H), 7.22-7.32 (m, 3H), 7.02-7.09 ( m, 1H), 6.09 (d, 1H), 6.01 (d, 1H), 5.76 (q, 1H), 5.38 (d, 2H), 2.35 (s, 3H), 2.02 (d, 3H). [ES + MS] m / z 418 (MH ^<+> ).

Chiral analytical HPLC conditions: CHIRALPAK-AD 4.6 × 150 mm column, method: constant rate elution mixture ACN 0.1% isoprilamine / MeOH 0.1% isopropylamine; ratio 85/15, flow rate: 1 mL / min. Rt: 4.43 minutes. αD = + 0.88 ⁰ . Absolute configuration was determined by non-empirical vibrational circular dichroism spectroscopy (VCD).

Example 67: N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1S) -1- (3-methyl-1H-pyrazole- 1-yl) ethyl] -1,3,4-thiadiazol-2-amine

Isomer 2, HPLC second eluent: 10.5 mg, white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.42 (d, 1H), 7.37 (d, 1H), 7.22-7.32 (m, 3H), 7.03-7.09 ( m, 1H), 6.09 (d, 1H), 5.99 (d, 1H), 5.76 (q, 1H), 5.38 (d, 2H), 2.35 (s, 3H), 2.02 (d, 3H). [ES + MS] m / z 418 (MH ^<+> ).

Chiral analytical HPLC conditions: CHIRALPAK-AD 4.6 × 150 mm column, method: constant rate elution mixture ACN 0.1% isoprilamine / MeOH 0.1% isopropylamine; ratio 85/15, flow rate: 1 mL / min. Rt: 6.70 minutes. αD = −1.47 ⁰ . Absolute configuration was determined by non-empirical vibrational circular dichroism spectroscopy (VCD).

Chiral separation of the racemate of Example 28

20 mg of Example 28 (racemic mixture) was separated using CHIRALPAK-AD 20 × 250 mm column, F = 17 mL / min, 254 nm using a mixture of hexane-ethanol 50:50. 20 mg was dissolved in a mixture of 32 mL of ethanol / isopropanol / methanol (methanol is the main solvent; the product is very insoluble) with heating. Sixteen injections were required to purify all samples. Since heating of the dissolved sample began during the injection, additional heating was required before each injection. Separation was complete and the relevant fractions were collected to give both enantiomers, then first on a 500 mg silica gel cartridge using DCM / MeOH (both solvents are HPLC grade) 25: 1 and finally, Reversed phase preparative HPLC (column SUNFIRE 19 × 150 mm, 3.5 mm; gradient H ₂ O-acetonitrile: 0 min 60:40; 3 min 60:40; 15 min 0: 100; 20 min 0: 100; 254 nm; F = 17 mL / To be purified. Corresponding fractions were collected to obtain the following compounds.

Example 68: N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1R) -1- (3,5-dimethyl-1H- Pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine

Isomer 1, first HPLC eluate: 3.5 mg, white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.36 (d, 1H), 7.22-7.33 (m, 3H), 7.04-7.10 (m, 1H), 5.97 ( d, 1H), 5.83 (s, 1H), 5.70 (q, 1H), 5.38 (d, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 2.00 (d, 3H). [ES + MS] m / z 432 (MH ^<+> ).

Chiral analytical HPLC conditions: CHIRALPAK-AD 4.6 × 150 mm column, method: constant rate elution mixture ACN 0.1% isoprilamine / MeOH 0.1% isopropylamine; ratio 85/15, flow rate: 1 mL / min. Rt: 2.67 minutes.

Example 69: N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1S) -1- (3,5-dimethyl-1H- Pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine

Isomer 2, HPLC second eluate: 1.7 mg, white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm: 7.36 (d, 1H), 7.23-7.33 (m, 3H), 7.04-7.10 (m, 1H), 5.97 ( d, 1H), 5.83 (s, 1H), 5.71 (q, 1H), 5.38 (d, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 2.00 (d, 3H). [ES + MS] m / z 432 (MH ^<+> ).

Chiral analytical HPLC conditions: CHIRALPAK-AD 4.6 × 150 mm column, method: constant rate elution mixture ACN 0.1% isoprilamine / MeOH 0.1% isopropylamine ratio 85/15, flow rate: 1 mL / min. Rt: 3.39 minutes.

Chiral separation of the racemate of Example 30

29 mg of Example 30 (racemic mixture) was added to a CHIRALPAK-AD 20 × 250 mm column, F = 17 mL / min, 254 nm and a constant rate mixture of ACN, 0.1% isopropylamine- (MeOH-iPrOH 60:40), 0.1% isopropylamine 90 : 10. The product was dissolved in 1.5 mL methanol (HPLC grade). After completion of the separation, the relevant fractions were collected to obtain the following enantiomers.

Example 70: (1S) -1- [5-({1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazole- 2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol

Chiral analytical HPLC conditions: CHIRALPAK-AD 4.6 × 150 mm column, method: constant rate elution mixture ACN 0.1% isoprilamine / (MeOH / isopropanol 60:40) 0.1% isopropylamine; ratio 90/10, flow rate: 1 mL / min . Rt: 6.02 minutes.

Example 71: (1R) -1- [5-({1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazole- 2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol

Chiral analytical HPLC conditions: CHIRALPAK-AD 4.6 × 150 mm column, method: elution mixture ACN 0.1% isoprilamine / (MeOH / isopropanol 60:40) 0.1% isopropylamine; ratio 90/10, flow rate: 1 mL / min. Rt: 15.20 minutes.

The compounds in Table 5 (Examples 72-82) were prepared using the procedures of Examples 1-28 described above (details of purification were given) and tested in InhA enzyme and TB growth inhibition assays.

a) The aqueous mixture was extracted with EtOAc. The organic extract was washed with brine, dried over sodium sulfate and concentrated.

b) The crude was purified by silica gel chromatography using a hexane / EtOAc gradient.

c) The crude was purified by silica gel chromatography using a DCM / MeOH gradient.

d) The residue was kneaded with ethanol, filtered and dried under vacuum.

e) The resulting precipitate was filtered, washed several times with water, and dried under vacuum.

f) Preparative HPLC was carried out under the conditions of an XTERRA chromatography column (19 mm × 150 mm), method (40 — 80) ACN (0.1% TFA) / H ₂ O (0.1% TFA).

Example 78: 1- [5-({1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1 -(4-Methyl-1,3-thiazol-2-yl) ethanol

A solution of intermediate 82 (168 mg, 0.835 mmol) and intermediate 70 (210 mg, 0.835 mmol) in ethanol (10 mL) was heated to reflux for 1 hour. A hydrazine carbothioamide intermediate was obtained ([ES + MS] m / z 453 (MH ⁺ ). The reaction mixture was concentrated.The residue was placed in an ice bath and sulfuric acid (3 mL, 0.835 mmol) was carefully added dropwise. The reaction mixture was placed in an ice bath and carefully treated with 37% aq.NH3 (15 mL) until the pH was basic, then the mixture was then EtOAc (100 mL). The organic components were washed with brine, dried over sodium sulfate and concentrated to give 360 mg of crude product, silica gel using a linear gradient, 0 → 70% EtOAc-Hex. ^. the title compound was purified by chromatography (130 mg, 35.8% yield) 1 H NMR (300MHz, DMSO- d 6) δppm: 10. 3 (br.s, 1H), 7.69 (d, 1H), 7.38-7.49 (m, 1H), 7.20-7.26 (m, 2H), 7.05-7. 15 (m, 2H), 5.93 (d, 1H), 5.25 (s, 2H), 2.29 (s, 3H), 1.97 (s, 3H) [ES + MS] m / z 435 ( MH ^<+> ).

The compounds in Table 6 (Examples 83-86) were prepared according to the procedure of Examples 1-28 described above (purification details are shown) and tested in InhA enzyme and TB growth inhibition assays.

a) The aqueous mixture was extracted with EtOAc. The organic extract was washed with brine, dried, dried over sodium sulfate and concentrated.

b) The crude was purified by silica gel chromatography using a DCM / MeOH gradient.

c) Preparative HPLC was performed under the conditions of an XBRIDGE chromatography column (19 mm × 150 mm), method (40 — 100) ACN / H ₂ O (0.1% NH ₄ CO ₃ 10 mM).

Example 87: N- {1-[(3-amino-2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazole- 1-yl) ethyl] -1,3,4-thiadiazol-2-amine

Intermediate 120 (N- {2,4-difluoro-3-[(3-isothiocyanato-1H-pyrazol-1-yl) methyl] phenyl} acetamide, 80 mg, 0.259 mmol) and intermediate 78 (2- (3 , 5-dimethyl-1H-pyrazol-1-yl) propanohydrazide, 48 mg, 0.259 mmol) in 5 ml DCM (anh) was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to give N- [3-({3-[({2- [2- (3,5-dimethyl-1H-pyrazol-1-yl) propanoyl] hydrazino} carbonothioyl) amino]. -1H-pyrazol-1-yl} methyl) -2,4-difluorophenyl] acetamide (145 mg, 0.296 mmol) was obtained as an orange solid ([ES + MS] m / z 491 (MH ^<+> )). This solid was dissolved in ₄ mL of concentrated H ₂ SO ₄ without further purification and stirred at room temperature for 45 minutes. The resulting mixture was neutralized with 32% NH ₃ (aq) in an ice bath until basic OH. The reaction mixture was then partitioned with AcOEt (x3) (15 mL). The organic layer was washed with distilled water (10 mL), dried over MgSO ₄ (anh), filtered and concentrated to give a solid which was obtained as ACN: NH ₄ CO ₃ (aq, 0.1%) (30_100) And purified by preparative HPLC: XBRIDGE_10. Two different compounds were isolated as solids and these were judged as the next two compounds from their properties.

Intermediate 122: N- (3-{[3-({5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-yl} Amino) -1H-pyrazol-1-yl] methyl} -2,4-difluorophenyl) acetamide

(20 mg, 0.042 mmol, 21% yield) ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.83 (br.s, 1H), 9.72 (br.s, 1H), 7.68 -7.86 (m, 2H), 7.01-7.11 (m, 1H), 5.95 (s, 1H), 5.84 (s, 1H), 5.75 (q, 1H), 5.26 (s, 2H), 2.24 (s, 3H), 2.10 (s, 3H), 2.05 (s, 3H), 1.79 (d, 3H), [ES + MS] m / z473 (MH +); and the title compound of Example 87: N- {1-[(3-amino-2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3 , 5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine ( 13 mgr, 0.030 mmol, 15% yield) ¹ HNMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.82 (br.s, 1H), 7.63 (s, 1H), 6.68-6.83 (M, 2H), 5.95 (s, 1H), 5.84 (s, 1H), 5.75 (q, 1H), 5.18 (s, 2H), 5.02 (s, 2H) 2.24 (s, 3H), 2.11 (s, 3H), 1.79 (d, 3H), [ES + MS] m / z 431 (MH +).

Example 88: 1- [5-({1-[(3-amino-2-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-Methyl-1,3-thiazol-2-yl) ethanol

Intermediate 121 ethyl (2-fluoro-3-{[3-({5 [-1-hydroxy-1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4, Thiadiazol-2-yl} amino) -1H-pyrazol-1-yl] methyl} phenyl) carbamate (108 mg, 0.214 mmol) was dissolved in 4 ml of THF (anh) under a nitrogen atmosphere. Next, N, N, N-tributyl-1-butanaminium fluoride (ALDRICH, 214 μL, 0.214 mmol) was added and the reaction mixture was heated to reflux. After 2 hours 45 minutes, more N, N, N-tributyl-1-butanaminium fluoride (ALDRICH, 214 μL, 0.214 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was diluted by adding 20 ml of THF, N, N, N-tributyl-1-butanaminium fluoride (ALDRICH, 214 μL, 0.214 mmol) was added and the temperature was fixed at 50 ° C. and 1 Stir for 30 minutes. The solvent was then removed in vacuo and the reaction crude was purified by silica chromatography using a DCM / MeOH (0-30-50%) gradient. A second purification on a SunFire chromatography column using a (25 — 100) ACN (0.1% formic acid) / water (0.1% formic acid) gradient as eluent gave the title compound as a white solid (15 mg, 15% ). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.84 (br.s.1H), 7.65 (d, 1H), 7.28 (s, 1H), 7.20 (s, 1H) 6.62-6.82 (m, 2H), 6.25-6.33 (m, 1H), 5.95 (d, 1H), 5.10-5.20 (m, 4H), 2 .29 (s, 3H), 1.79 (s, 3H). [ES + MS] m / z 432 (MH ^<+> ).

Chiral separation of the racemate of example 78

78 mg of Example 78 (racemic mixture) was added to a CHIRALPAK-AD 20 × 250 mm column, F = 17 mL / min, 254 nm, and an isocratic mixture ACN, 0.1% isopropylamine- (MeOH-iPrOH 60:40), 0.1% isopropyl Separated using amine 90:10. The product was dissolved in 3.5 mL MeOH / ACN (1 mL MeOH and 2.5 mL ACN, HPLC grade). Complete injection required two injections. After completion of the separation, the corresponding fractions were collected to obtain the following enantiomers.

Example 89: (1S) -1- [5-({1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazole-2- Yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol

Isomer 1, first HPLC eluate: 28 mg, pale orange solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.82 (br.s, 1H), 7.69 (s, 1H), 7.39-7.49 (m, 1H), 7.24 ( s, 1H), 7.22 (s, 1H), 7.06-7.14 (m, 2H), 5.93 (s, 1H), 5.25 (s, 2H), 2.29 (s) 3H), 1.97 (s, 3H). [ES + MS] m / z 435 (MH ^<+> ).

Chiral analytical HPLC conditions: CHIRALPAK-AD-H 4.6 × 150 mm column, method: constant rate elution mixture ACN, 0.1% isopropylamine- (MeOH-iPrOH 60:40), 0.1% isopropylamine; ratio 90:10, flow rate: 1 mL / min. Rt: 3.89 minutes. α _D = + 101.55 ⁰ . Absolute configuration was determined by non-empirical vibrational circular dichroism spectroscopy (VCD).

Example 90: (1R) -1- [5-({1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazole-2- Yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol

Isomer 2, HPLC second eluent: 41 mg, pale yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 10.83 (br.s, 1H), 7.69 (s, 1H), 7.39-7.49 (m, 1H), 7.24 ( s, 1H), 7.22 (s, 1H), 7.06-7.14 (m, 2H), 5.93 (s, 1H), 5.25 (s, 2H), 2.29 (s) 3H), 1.97 (s, 3H). [ES + MS] m / z 435 (MH ^<+> ).

Chiral analytical HPLC conditions: CHIRALPAK-AD-H 4.6 × 150 mm column, method: constant rate elution mixture ACN, 0.1% isopropylamine- (MeOH-iPrOH 60:40), 0.1% isopropylamine ratio 90:10, flow rate: 1 mL / Min. Rt: 5.93 minutes. αD = −96.08 ⁰ . Absolute configuration was determined by non-empirical vibrational circular dichroism spectroscopy (VCD).

Biological activity
Mycobacterium tuberculosis H37Rv inhibition assay (whole cell assay)
Measurement of minimum inhibitory concentration (MIC) for each tested compound was performed in a 96 well flat bottom polystyrene microtiter plate. A 2-fold drug dilution of anhydrous DMSO was performed 10 times starting from 400 μM. 5 μl of these drug solutions were added to 95 μl of Middlebrook 7H9 medium. (AH row, 1-10 columns of plate layout). Using isoniazid as a positive control, eight 2-fold dilutions of isoniazid starting from 160 μg / ml were prepared and 5 μl of this control curve was added to 95 μl of Middlebrook 7H9 medium (Difco catalogue ref. 271310). (Column 11, Rows AH). 5 μl of anhydrous DMSO was added to row 12 (growth and blank controls).

The inoculum is normalized to approximately 1 × 10 ⁷ cfu / ml and is 1 to 100 in Middlebrook 7H9 medium (for growth of the Middlebrook ADC, dehydrated growth medium available from Becton Dickinson catalog number 2111887). To obtain the final inoculum H3Rv strain (ATCC 25618). 100 μl of this inoculum was added to the entire plate except G-12 well and H-12 well (blank control). All plates were placed in a sealed box to prevent the surrounding wells from drying and incubated at 37 ° C. for 6 days without shaking. The resazurin solution was prepared by dissolving 1 resazurin tablet (Resazurin Tables for Milk Testing; Ref 3308104Y VWR International Ltd) in 30 ml of sterile PBS (phosphate buffered saline). 25 μl of this solution was added to each well. After 48 hours, fluorescence was measured (Spectramax M5 Molecular Devices, excitation wavelength 530 nm, fluorescence wavelength 590 nm) to determine the MIC value.

Results of Mycobacterium tuberculosis H37Rv inhibition assay (whole cell assay) Unless otherwise noted below, all examples were tested in a whole cell assay. Intermediates 121 and 122 were also tested in this assay.

  Examples 7, 10, 12, 13, 23, 24, 28, 30, 38, 70, 76-81, 83, 84, 86 and 89 described above were found to have MIC values of 1 μM or less. . For example, Example 89 was found to have a MIC value of 0.2 μM.

  Examples 3, 6, 14-16, 19, 20, 22, 25, 29, 33, 39, 40, 42, 44, 54, 66, 67, 69, 71, 72, 74, 85, 87 and above Intermediate 121 was found to have a MIC value below 4 μM and above 1 μM.

  It was revealed that Examples 1, 4, 5, 21, 27, 32, 34, 36, 37, 41, 43 and 82 described above have MIC values of 10 μM or less and greater than 4 μM.

  Examples 2, 8, 9, 11, 17, 18, 26, 31, 35, 45-53, 55-64, 68, 73, 75, 90 and intermediate 122 described above have MIC values greater than 10 μM. It became clear.

  Example 65 was not tested in a whole cell assay.

  In one aspect, the compounds of the invention have a MIC value of 4 μM or less in the Mycobacterium tuberculosis H37Rv inhibition assay (whole cell assay).

Mycobacterium tuberculosis InhA inhibition assay (enzyme assay)
InhA can reduce 2-transenoyl CoA ester with concomitant oxidation of NADH to NAD ⁺ . The assay format is based on kinetic detection of NADH consumption.

InhA inhibition assay was performed with purified forms of E. coli expressing mycobacterial recombinant proteins. Standard assay conditions for measuring kinetic constants and inhibitory activity use 5 nM InhA, and 50 μM Dodecenoyl-CoA synthesized and purified as described by Queueard et al (DDCoA), and 50 μM NADH as substrate. In addition, the assay was performed in 30 mM PIPES buffer (pH 6.8) containing 0.05% BSA. Solutions of test compounds were prepared in 100% DMSO; eight 3-fold dilutions starting from 25 μM (or 1 μM for the most potent compounds) were made to generate dose response curves. Triclosan was used as a positive control in all experiments. 1 μl of compound was added to a well containing 25 μl of DDCoA + NADH mixture and 50 μl of enzyme solution was added to initiate the reaction. Fluorescence from NADH was followed with a fluorescent plate reader for 20 minutes at room temperature (excitation at 340 nM; emission at 480 nM). IC ₅₀ values were determined using the initial rate of NADH consumption.

  Qualard A, Sacchettini JC, Dessen A, et al, target enzyme characterization for isoniazid in Mycobacterium tuberculosis, Biochemistry 1995; 34: 8235-41.

M. tuberculosis InhA inhibition assay (enzyme assay) results All samples were tested in an enzyme assay unless otherwise stated below. Intermediates 121 and 122 were also tested in this assay.

Examples 1-16, 19-33, 36-43, 46, 47, 49-51, 53-57, 66-72, 74, 76-89 and intermediate 121 are less than 0.05 μg / ml It was found to have an IC ₅₀ value. For example, Example 89 was found to have an IC ₅₀ value of 0.002 μg / ml.
Examples 17, 18, 34, 44, 45, 48, 52, 73, 75, 90 and intermediate 122 described above may have IC ₅₀ values less than 0.10 μg / ml and greater than 0.05 μg / ml. It was revealed.
Examples 35 and 58-64 described above were found to have IC ₅₀ values less than 0.50 μg / ml and greater than 0.10 μg / ml.

Example 65 described above was found to have an IC ₅₀ value of greater than 0.50 μg / ml.

In one aspect, the compounds of the invention have an IC ₅₀ value of less than 0.05 μg / ml in a Mycobacterium tuberculosis InhA inhibition assay (enzyme assay).

  Whether all publications, including but not limited to the patents and patent applications cited in this specification, have the indication that each publication is specifically and individually incorporated by reference in its entirety. As is incorporated herein by reference.

  The application of which this description and claims are part may be the basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of claims relating to products, compositions, processes, or uses, and may include, by way of example and not limitation, the following claims.

Claims (14)

Compound of formula (I):

(Where
X is N and Y is CR ⁵ ; or X is C and Y is S;
Z is selected from N and CH;
R ¹ is selected from H and Me;
R ² is selected from H, OH, OMe and Me;
Each R ³ is independently selected from C _1-3 alkyl, F, Cl, Br, CF ₃ and NH ₂ ;
R ⁴ is selected from Me, CF ₃ , NO ₂ and CHF ₂ ;
R ⁵ is selected from H, Me and CHF ₂ ;
R ⁶ is selected from H and Me; and p is 0-3),
Or an agent for treating tuberculosis, comprising a pharmaceutically acceptable salt thereof. N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1 3,4-thiadiazol-2-amine N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3-methyl-1H-pyrazole- 1-yl) methyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (5-methyl) -3-nitro-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl}- 5- {1- [3- (Difluoromethyl -5-methyl-1H-pyrazol-1-yl] ethyl} -1,3,4-thiadiazol-2-amine N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl}- 5- [1- (3-Methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 5- {1- [3- (difluoromethyl) -5-methyl-1H -Pyrazol-1-yl] ethyl} -N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazol-2-amine 5- [1- (3-methyl- 1H-pyrazol-1-yl) ethyl] -N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazol-2-amine 5-{[3- (difluoromethyl ) -5-Methyl-1H-pi Zol-1-yl] methyl} -N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chlorophenyl) Methyl] -1H-pyrazol-3-yl} -5-{[3- (difluoromethyl) -5-methyl-1H-pyrazol-1-yl] methyl} -1,3,4-thiadiazol-2-amine N -{1-[(2,6-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3-nitro-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazole -2-amine N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5-{[5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] Methyl} -1,3, 4-thiadiazol-2-amine N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3-nitro-1H-pyrazol-1-yl) methyl] -1 3,4-thiadiazol-2-amine N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(5-methyl-3-nitro- 1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl}- 5-[(3,5-Dimethyl-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazole-3- L} -5-[(3-nitro-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine N- {1-[(2,6-dichlorophenyl) methyl] -1H -Pyrazol-3-yl} -5-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine N- {1-[(2,6 -Dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- { 1-[(2-Chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-{[3- (difluoromethyl) -5-methyl-1H-pyrazol-1-yl] methyl} -1,3,4-thiadiazole- -Amine N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1,3, 4-thiadiazol-2-amine N- {1-[(2,6-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(3-methyl-1H-pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(5-methyl-3-nitro-1H-pyrazole -1-yl) methyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5-{[3- (tri Fluoromethyl) -1H-pyrazo Ru-1-yl] methyl} -1,3,4-thiadiazol-2-amine 5-[(3-methyl-1H-pyrazol-1-yl) methyl] -N- [1- (phenylmethyl) -1H -Pyrazol-3-yl] -1,3,4-thiadiazol-2-amine N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -5-{[3- (trifluoromethyl)- 1H-pyrazol-1-yl] methyl} -1,3,4-thiadiazol-2-amine 5-[(5-methyl-3-nitro-1H-pyrazol-1-yl) methyl] -N- [1- (Phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazole-3- Il} -5-{[3- (Triff Olomethyl) -1H-pyrazol-1-yl] methyl} -1,3,4-thiadiazol-2-amine 5-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -N- [1 -(Phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazol-2-amine and N- {1-[(2,6-dichlorophenyl) methyl] -1H-pyrazol-3-yl } -5- [1- (5-methyl-3-nitro -1H- pyrazol-1-yl) methyl] -1,3,4-thiadiazol-2-is the reduction compound selected from an amine, or a pharmaceutically An agent for the treatment of tuberculosis, including an acceptable salt thereof. Compound of formula (I ^* ):

(Where
X is N and Y is CR ⁵ ; or X is C and Y is S;
Z is selected from N and CH;
R ¹ is Me;
R ² is selected from H, OH, and OMe;
Each R ³ is independently selected from C _1-3 alkyl, F, Cl, Br, CF ₃ and NH ₂ ;
R ⁴ is selected from Me, CF ₃ , NO ₂ and CHF ₂ ;
R ⁵ is selected from H, Me and CHF ₂ ;
R ⁶ is selected from H and Me; and p is 0-3),
Or a pharmaceutically acceptable salt thereof. N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1S) -1- (3-methyl-1H-pyrazol-1-yl) Ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(1S) -1 -(3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine and (1S) -1- [5-({1-[(2-chloro- 6-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol And (1S) -1- [5-({1-[(2,6- Fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol Or a pharmaceutically acceptable salt thereof.   (1S) -1- [5-({1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1 A compound which is (4-methyl-1,3-thiazol-2-yl) ethanol, or a pharmaceutically acceptable salt thereof. Compound of formula (I):

(Where
X is C and Y is S;
Z is selected from N and CH;
R ¹ is selected from H and Me;
R ² is selected from H, OH, OMe and Me;
Each R ³ is independently selected from C _1-3 alkyl, F, Cl, Br, CF ₃ and NH ₂ ;
R ⁴ is selected from Me, CF ₃ , NO ₂ and CHF ₂ ;
R ⁶ is selected from H and Me; and p is 0-3),
Or a pharmaceutically acceptable salt thereof. 5- [1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -N- (1-{[2- (trifluoromethyl) phenyl] methyl} -1H-pyrazol-3-yl) -1,3,4-thiadiazol-2-amine N- {1-[(2,5-dichlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H -Pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-bromophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(2,5-dichlorophenyl) methyl] -1H-pyrazole-3 -Yl} -5- [1- (3-methyl- H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-bromophenyl) methyl] -1H-pyrazol-3-yl} -5- [1 -(3-Methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- {1-[(2-fluorophenyl) methyl] -1H-pyrazol-3-yl} -1,3,4-thiadiazol-2-amine N- {1-[(3-chloro-2-fluoro Phenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- (1-{[2,5-bis (trifluoro Til) phenyl] methyl} -1H-pyrazol-3-yl) -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 5- [1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -N- (1-{[5-fluoro-2- (trifluoromethyl) phenyl] methyl} -1H-pyrazole- 3-yl) -1,3,4-thiadiazol-2-amine N- {1-[(2,3-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3, 5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- (1-{[2-chloro-5- (trifluoromethyl) phenyl] methyl} -1H -Pyrazol-3-yl) -5 [1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(2,6-difluorophenyl) methyl] -1H -Pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(2 -Fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazole-2 -Amine N- {1-[(3-chloro-2-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine -{1-[(2,3-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3, 4-thiadiazol-2-amine N- {1-[(2,3-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (4-methyl-1,3-thiazole-2) -Yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chloro-4-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chloro-4-fluorophenyl) methyl] -1H- Pyrazol-3-yl} -5- [1- (3-me Ru-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chloro-6-fluorophenyl) methyl] -5-methyl-1H-pyrazole -3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine 5- [1- (3,5- Dimethyl-1H-pyrazol-1-yl) ethyl] -N- {1-[(2-methylphenyl) methyl] -1H-pyrazol-3-yl} -1,3,4-thiadiazol-2-amine 5- [1- (3,5-Dimethyl-1H-pyrazol-1-yl) ethyl] -N- [1- (phenylmethyl) -1H-pyrazol-3-yl] -1,3,4-thiadiazole-2- Amine N- {1-[(6-chloro-2-fur Oro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazole- 2-Amine N- {1-[(2-chloro-6-fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazole -1-yl) ethyl] -1,3,4-thiadiazol-2-amine 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- {1-[(2 -Fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -1,3,4-thiadiazol-2-amine N- {1-[(2-fluoro-3-methylphenyl) methyl]- 1H-pyrazol-3-yl} -5- [ -(4-Methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(5-amino-2-chlorophenyl) methyl] -1H- Pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(3- Amino-2-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazole- 2-Amine N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ) Ethyl] -1,3,4-thiadiazole-2 Amine N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (4-methyl-1,3-thiazol-2-yl) ethyl ] -1,3,4-thiadiazol-2-amine 1- [5-({1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3 4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazole -3-yl} -5- {1- [4- (trifluoromethyl) -1,3-thiazol-2-yl] ethyl} -1,3,4-thiadiazol-2-amine N- {1- [ (2-Chloro-6-fluorophenyl) methyl] -1H -Pyrazol-3-yl} -5-[(4-methyl-1,3-thiazol-2-yl) methyl] -1,3,4-thiadiazol-2-amine N- {1-[(3-chloro -2-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazole-2 -Amine N- {1-[(4-chlorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1, 3,4-thiadiazol-2-amine 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- (1-{[4- (trifluoromethyl) phenyl] methyl} -1H-pyrazol-3-yl) -1,3,4-thi Diazol-2-amine N- {1-[(2-chloro-5-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazole-1 -Yl) ethyl] -1,3,4-thiadiazol-2-amine and N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[( 3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof. N- {1-[(2-chloro-6-fluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (methyloxy) -1- (4-methyl-1,3-thiazole -2-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5-[(methyl Oxy) (4-methyl-1,3-thiazol-2-yl) methyl] -1,3,4-thiadiazol-2-amine N- {1-[(2-chloro-6-fluorophenyl) methyl]- 1H-pyrazol-3-yl} -5- [1-methyl-1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazol-2-amine 5- [ 1- (3,5-Dimethyl-1H-pyrazol-1-yl Ethyl] -N- {1 - [(4- fluorophenyl) methyl]-1H-pyrazol-3-yl} -1,3,4-thiadiazol-2-amine
N- {1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3 , 4-thiadiazol-2-amine 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- {1-[(2,3,6-trifluorophenyl) methyl] -1H-pyrazol-3-yl} -1,3,4-thiadiazol-2-amine 1- [5-({1-[(2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} Amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol 1- [5-({1-[(3-chloro-2 -Fluorophenyl) methyl] -1H-pyrazol-3-yl} Amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol 1- [5-({1-[(2,3-difluoro Phenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol N- { 1-[(2,6-Difluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl]- 1,3,4-thiadiazol-2-amine and 5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -N- (1-{[2- (ethyloxy) -3, 6-Difluorophenyl] methyl} -1H-pyrazo 3-yl) -1,3,4-thiadiazol-2 compound is selected from amine or a pharmaceutically acceptable salt thereof. 1- [5-({1-[(2-Fluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- ( 4-methyl-1,3-thiazol-2-yl) ethanol 1- [5-({1-[(2,6-difluoro-3-methylphenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazol-2-yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol N- {1-[(2,6-difluoro-3-methylphenyl) Methyl] -1H-pyrazol-3-yl} -5- [1- (4-methyl-1,3-thiazol-2-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1 -[(2,6-difluoro-3-methylphenyl) methyl -1H-pyrazol-3-yl} -5- [1- (3-methyl-1H-pyrazol-1-yl) ethyl] -1,3,4-thiadiazol-2-amine N- {1-[(3 -Amino-2,6-difluorophenyl) methyl] -1H-pyrazol-3-yl} -5- [1- (3,5-dimethyl-1H-pyrazol-1-yl) ethyl] -1,3,4 -Thiadiazol-2-amine and 1- [5-({1-[(3-amino-2-fluorophenyl) methyl] -1H-pyrazol-3-yl} amino) -1,3,4-thiadiazole-2 -Yl] -1- (4-methyl-1,3-thiazol-2-yl) ethanol, or a pharmaceutically acceptable salt thereof. 請 Motomeko 3 A compound according to any one of to 9 or a pharmaceutically including acceptable salt thereof, TB therapeutic agents.   Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of tuberculosis. A pharmaceutical composition comprising a compound according to any one of claims 3 to 9, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents. . Compounds of formula (I) according to any one of claims 3-9 or in addition to a pharmaceutically acceptable salt thereof, combinations comprising one or more additional therapeutic agents. 14. A combination according to claim 13, wherein the one or more additional therapeutic agents are anti-tuberculosis agents.